ITRM20070599A1 - PROLONGED RELEASE COMPOSITIONS AND PROCEDURES FOR THEIR MANUFACTURE. - Google Patents

Description

DESCRIPTION

In support of an application for an Invention Patent entitled:

"Prolonged-release compositions and processes for their manufacture"

Cross-reference to related question

This is a non-provisional of the U.S. Provisional Application. No. 60/930 643, filed May 16, 2007, which is incorporated herein by reference in its entirety.

Field of Invention

The present invention relates to a formulation 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1.4] thiazepine (quetiapine). More particularly, the invention relates to a prolonged release pharmaceutical composition which contains quetiapine or a pharmaceutically acceptable salt thereof.

Anterior technique

The compound 11- [4 [2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine (see Form-mula 1), having the common name "quetiapine" and related pharmaceutically acceptable salts, exhibits useful antidopaminergic activity and can be used, for example, as an antipsychotic agent (for example, for the treatment of manifestations of psychotic disorders) or as a treatment for hyperactivity. The compound can be used as an antipsychotic agent. with a substantial reduction in the potential to cause secondary effects such as acute dystonia, acute dyskinesia, pseudo-Parkinsonism and tardive dyskinesia, which secondary effects may result from the use of typical antipsychotics or neuroleptics.

Formula 1

The preparation, physical properties and favorable pharmacological properties of quetiapine and its pharmaceutically acceptable salts are described in European Patent Nos. 240 228 and 282,236 and in U.S. Pat. No. 4 879 288, the contents of which are incorporated herein by reference in their entirety.

It is desirable in the treatment of a number of diseases, both therapeutically and prophylactically, to provide an active pharmaceutical ingredient in a sustained release form. The sustained release can provide a generally uniform and constant rate of release over an extended period of time and can achieve a desired blood plasma or blood level of the active ingredient without the need for frequent administration of the ingredient. .

While there are a number of sustained release compositions known in the art that utilize gelling agents, such as hydroxy propyl methyl cellulose (also referred to hereinafter as "HPMC" and "hypromellose"), it has been found to be difficult to formulate medical sustained release formulations. -soluble elements and gelling agents, such as hypromellose, for several reasons. Primarily, it has been found to be difficult to achieve the desired dissolution profiles or to control the rate of release of the active ingredients which are soluble in aqueous media (as is the case with quetiapine, which is slightly soluble in water and soluble in acid). Among other problems, such active ingredients tend to generate a sustained release product which is susceptible to a phenomenon known as dose dumping. That is, the release of the active ingredient is delayed for a certain time but once the release begins to occur the release rate is very high. Furthermore, fluctuations tend to occur in the plasma concentrations of the active ingredient, thereby increasing the likelihood of toxicity. Further, some degree of daily variation in the plasma concentration of the active ingredient was also observed.

Because of the numerous physical and chemical interactions between the constituents of some pharmaceutical compositions, it is also often difficult to combine the constituents in a manner that provides a formulation with the desirable physical or chemical characteristics.

In accordance with the foregoing, it would be desirable to provide prolonged release formulations of water-soluble medicinals, such as il- [4 [2 (2-hydroxy ethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1 , 4] thiazepine or a pharmaceutically acceptable salt which provides improved performance and can overcome or at least alleviate one or more of the difficulties described above.

Summary

Formulations are provided which include quetiapine and its pharmaceutically acceptable salts and manufacturing processes of the formulations.

One formulation may include a hydrophilic matrix which includes a gelling agent, the— [4— [2— (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo

[b, f] [1,4] thiazepine, or a pharmaceutically acceptable salt thereof, such as a hemifumarate salt and one or more pharmaceutically acceptable excipients.

Examples of gelling agents which may be present in the embodiments of the invention include such substances as hydroxy propyl cellulose, hydroxy methyl cellulose, hydroxy ethyl cellulose, hydroxy propyl ethyl cellulose, methyl cellulose, ethyl cellulose, carboxy ethyl cellulose. , carboxymethyl hydroxy ethyl cellulose, carbomer, sodium carboxy methyl cellulose, polyvinyl pyrrolidone and the like, or mixtures thereof. In certain embodiments, the gelling agent may comprise hypromellose.

The amount of gelling agent, in combination with the quetiapine and any excipient, can be selected such that the active ingredient is released from the formulation, in a controlled manner, over a period of approximately 24 hours.

The gelling agent may be present in a range of about 5 to 50% (by weight). The range can be about 5 to 10%. The range can be about 20 to 50%. The range may be about 25 to 50%. The range can be from 28 to 50%. The range can be 30 to 50%. (Percentages by weight, as used herein, are relative to the weight of tablets with a core, excluding the weight of any liner, unless otherwise specified.)

Some embodiments of the invention may include hypromellose mixtures which include more than one gradation of polymers. Hypro-mellose polymers are commercially available under several trade names, for example METHOCEL® E, F, J and K from the Dow Chemical Company, U.S.A. and METOLOSE ™ 60SH, 65SH and 90SH from Shin-Etsu, Ltd., Japan. Grades may have differences in hydroxy propoxy and methoxy content as well as viscosity and other characteristics. Different batches of hypromellose, even of the same gradation, can have differences in the contents of hydroxy propoxy and methoxy, in viscosity and in other characteristics.

The formulation may contain a buffer or a pH modifying agent, for example if the active ingredient exhibits pH dependent solubility, as is the case for quetiapine salts such as quetiapine fumarate.

The formulation will generally contain one or more excipients. Such excipients may include diluents such as lactose, microcrystalline cellulose, dextrose, mannitol, sucrose, sorbitol, gelatin, acacia, dicalcium phosphate, tricalcium phosphate, monocalcium phosphate, sodium phosphate, sodium carbonate and the like, preferably lactose. and microcrystalline cellulose; lubricants such as stearic acid, zinc, magnesium or calcium stearate and the like, preferably magnesium stearate; binders such as sucrose, polyethylene glycol, povidone (polyvinyl pyrrolidone), ce-royal starch or corn starch, pregelatinised starch and the like; dyes such as ferric oxides, FD & C dyes, lacquers and the like; flavoring agents; and pH modifying agents which include suitable organic acids or alkali metal salts thereof (e.g., lithium, sodium or potassium), such as benzoic acid, citric acid, tartaric acid, succinic acid and adipic acid and the like or the corresponding metal salts alkaline, preferably the alkali metal salts of such acids and in particular the sodium salt of citric acid (i.e. sodium citrate). As is well known, some excipients have multiple functions, such as being both diluents and binders.

In some embodiments of the invention, the formulation may be present in a solid dosage form such as a tablet, caplet (ovoid tablet) or any other suitable form comprising 11- [4 [2 (2-hydroxyethoxy) ethyl] -1 -piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate ("quetiapine fumerate"), from 6 to 18% by weight of sodium citrate dihydrate, hydroxy propyl methyl cellulose at 30.0% by weight, wherein 15-29 of 30.0% is a first constituent of hydroxy propyl methyl cellulose; the remainder of 30.0% is a second constituent of hydroxy propyl methyl cellulose; and the first and second constituents correspond, respectively, to a first gradation of hydroxy propyl methyl cellulose which propyl methyl cellulose which has an "apparent viscosity" (see below) between 80 centipoise ("cp") and 120 cp and a second hydroxy propyl methyl cellulose which has an apparent viscosity between 3000 cp and 5600 cp. sticca may comprise 11-12% by weight of 11— [4— [2— (2— hydro xxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate. The tablet may comprise 29.5-30.5% by weight of 11- [4- [2- (2-hydroxy ethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate. The tablet may comprise 37.9-38.9% by weight of 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate. In some embodiments, the tablet comprises 52.4-53.4% by weight of 11- [4- [2- (2-hydroxyethoxy) ethyl] -1piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate.

In some embodiments, the viscosities of the hydroxy propyl methyl cellulose are consistent with the apparent viscosities of the Ubbelohde viscometer of 2 wt% hydroxy propyl methyl cellulose in water at 20 °, as determined using the method described in The United States Pharmacopoeia (USP30-NF25), United States Pharmacopoeia Convention, Inc. 2007, page 2323.

In some embodiments of the invention, the formulation comprises sodium citrate dihydrate present in about 7.2-12.5% by weight. In some embodiments, the formulation comprises sodium citrate dihydrate present at 7.2% by weight. In some embodiments, the formulation comprises sodium citrate dihydrate present at 11.5% by weight. In some embodiments, the formulation comprises sodium citrate dihydrate present at 12.5% by weight.

In some embodiments of the invention, the formulation comprises lactose monohydrate present up to a maximum of about 30% by weight. In some embodiments, the formulation comprises lactose monohydrate present in 25.1% by weight. In some embodiments, the formulation comprises lactose monohydrate present in 13.0% by weight. In some embodiments, the formulation comprises lactose monohydrate present in 8.8% by weight. In some embodiments, the formulation comprises lactose monohydrate present in 1.8% by weight.

In some embodiments, the formulation comprises microcrystalline cellulose present up to a maximum of about 30% by weight. In some embodiments, the formulation comprises microcrystalline cellulose present in 25.1% by weight. In some embodiments, the formulation comprises microcrystalline cellulose present in 13.0% by weight. In some embodiments, the formulation comprises microcrystalline cellulose present in 8.8% by weight. In some embodiments, the formula comprises microcrystalline cellulose present in 1.8% by weight.

In some embodiments, the tablet comprises an amount of magnesium stearate about 1% to 3% by weight. In some embodiments, the tablet comprises magnesium stearate present in 1.0% by weight. In some embodiments, the paste comprises magnesium stearate present in 1.5% by weight. In some embodiments, the paste comprises magnesium stearate present in 2.0% by weight.

In some embodiments, hydroxy propyl methyl cellulose comprises 9.8 to 13.4 wt% hydroxy propyl methyl cellulose, as measured by nuclear magnetic resonance ("NMR"), hydroxy propoxy. In some embodiments, hydroxy propyl methyl cellulose comprises 26.4 to 29.2% by weight of the hydroxy propyl methyl cellulose, as measured by NMR, methoxy.

In some embodiments of the invention, the solid dosage form comprises 50 milligrams ("mg") of quetiapine, for example in a total core mass of 500 mg. In some embodiments, the dosage form solid comprises 150 mg of quetiapine, for example, in a total core mass of 575 mg. In some embodiments, the solid dosage form comprises 200 mg of quetiapine, for example in a total mass of quetiapine. central part of 600 mg In some embodiments, the solid dosage form comprises 400 mg of quetia-pine, for example in a total core mass of 870 mg.

In some embodiments of the invention, the formulation is present in a solid dosage form comprising 50 mg of quetiapine, the dosage form, after ingestion under steady state conditions by a human. resulting in a concentration in the blood plasma, in nanograms, of quetiapine per milliliter of plasma, which is up to about: 67.6 at one hour after ingestion; 124 to 4 hours after ingestion; 105 to 8 hours after ingestion; 74.3 to 12 hours after ingestion; and 236 at 16 hours after ingestion.

In some embodiments of the invention, the formulation is a solid dosage form comprising 200 mg of quetiapine, the dosage form, after ingestion under steady-state conditions by a human, resulting in a concentration in blood plasma, in nanograms of quetiapine per milliliter of plasma, that is: up to about 251 to one hour after ingestion; between about 32.2 and about 416 to 4 hours after ingestion; up to a maximum of approximately 496 to 8 hours after ingestion; between about 4.6 and about 323 to 12 hours after ingestion; and up to a maximum of approximately 251 to 16 hours after ingestion.

In some embodiments of the invention, the formulation is a solid dosage form comprising 400 mg of quetiapine, the dosage form, after ingestion under steady-state conditions by a human, resulting in a concentration in blood plasma, in nanograms of quetiapine per milliliter of plasma, which is: between about 15.9 and about 391 at one hour after ingestion; until about 1052 to 4 hours after ingestion; between about 63.1 and about 785 to 8 hours after ingestion; between about 11.1 and about 613 to 12 hours after ingestion; and up to a maximum of approximately 448 to 16 hours after ingestion.

In some embodiments of the invention, a dosage form comprises: 30.0% by weight of hydroxy propyl methyl cellulose and 7.2% of sodium citrate dihydrate. In certain embodiments, 15-29 of 30.0% is a first constituent of hydroxy propyl methyl cellulose; the remainder of 30.0% is a second constituent of hydroxy propyl methyl cellulose; and the first and second constituents correspond, respectively, to a first gradation of hydroxy propyl methyl cellulose which has an apparent viscosity between 80 cp and 120 cp and a second hydroxy propyl methyl cellulose which has an apparent viscosity between 3000 cp and 5600 cp. In some embodiments, the viscosities of the dosage form are consistent with the apparent viscosities of the Ubbelohde viscometer of 2% by weight hydroxy propyl methyl cellulose in water at 20 °, as determined using the method described in The United States Pharmacopoeia (USP30-NF25), United States Pharmacopoeia Convention, Ine. 2007, page 2323. In some embodiments, the first and second constituents, respectively, have viscosities of 80-120 cp and 3000-5600 cp.

In some embodiments of the invention, a solid dosage form comprises 50 mg of quetiapine, the dosage form, after ingestion under steady-state conditions by a human, resulting in a concentration dependent on the quetiapine time in blood plasma, in quetiapine in nanograms per milliliter of plasma, having a maximum value, Cmax, which is up to about 239 and corresponds to a time tmax which is between 2 and 16 hours after ingestion. In some embodiments, the concentration has a value of C24, which is up to about 39.2 and corresponds to a time t24, 24 hours after ingestion; and the ratio Cmax · C24 is up to about 35.2.

In some embodiments of the invention, a solid dosage form comprises 200 mg of que-thiapine, the dosage form, after ingestion under steady-state conditions by a human, resulting in a time-dependent concentration of quetiapine in blood plasma, in quetiapine in nanograms per milliliter of plasma, having a maximum value, Cmax, which is between about 3.9 and about 601 and corresponds to a time tmax which is between 2 and 8 hours after ingestion. In some embodiments, the concentration has a value of C24, which is up to about 156 and corresponds to a time t24, 24 hours after ingestion; and the ratio Cmax: C24 is up to about 20.9.

In some embodiments of the invention, a solid dosage form comprises 400 mg of que-thiapine, the dosage form, after ingestion under steady-state conditions by a human, resulting in a concentration-dependent concentration. quetiapine time in blood plasma, in que-thiapine in nanograms per milliliter of plasma, having a maximum value, Cmax, which is between about 80 and about 1109 and corresponds to a time tmax which is between 3 and 8 hours after ingestion. In some embodiments, the concentration has a value of C24, which is up to about 265 and corresponds to a time t24, 24 hours after ingestion; and the ratio Cmax: C24 is up to about 25.9.

In some embodiments of the invention a solid dosage form comprises 50 mg of quetia-pine, the dosage form, after ingestion under steady-state conditions by different humans, resulting in distinct, dependent concentrations. from the time of quetiapine in the blood plasma, which have a maximum value, C mean max / between about 5.1 and about 117 nanograms of quetiapine per milliliter of plasma, C mean max corresponding to a time that is between 2.5 and 3.5 hours after the ingestion. In some embodiments, the distinct concentrations have an average value C, 24 which is about 14.8 and corresponds to a time of 24 hours after ingestion; and the ratio Cmedia max: Cmedia, 24 is about 4.1.

In some embodiments of the invention, a solid dosage form comprises 200 mg of que-thiapine, the dosage form, after ingestion under steady-state conditions by different humans, resulting in distinct time-dependent concentrations of quetiapine in blood plasma, which have a maximum value, C average max / which is up to about 550.4 nanograms of quetiapine per milliliter of plasma, C average max / corresponding to a time that is between 5.5 and 6.5 hours after ingestion. In some embodiments, the distinct concentrations have an average value C, 24 which is about 64.9 and corresponds to a time of 24 hours after ingestion; and the ratio Cmediamax · Cmedia, 24C about 4.0.

In some embodiments of the invention, a solid dosage form comprises 400 mg of quetiapine, the dosage form, after ingestion under steady-state conditions by different humans, resulting in distinct time-dependent concentrations of quetiapine in the blood plasma, which have a maximum value, C average maXf which is up to about 1062 nanograms of quetiapine per milliliter of plasma, C average maxi corresponding to a time that is between 2.5 and 3.5 hours after ingestion. In some forms of realization, the distinct concentrations have an average value C, 24 which is about 114 and corresponds to a time of 24 hours after ingestion; and the Cmedia report

maxCmedia, 24C Approx.4. 6.

In some embodiments of the invention, a solid dosage form comprises 50 mg of quetiapine, the dosage form, after ingestion under steady-state conditions by different humans, resulting in distinct time-dependent concentrations. quetiapine in blood plasma, which have a cumulative area under the curve, AUC-CUm, which is: up to 46 to one hour after ingestion; between 8 and 352 to 4 hours after ingestion; between 34 and 789 to 8 hours after ingestion; between 83 and 1092 to 12 hours after ingestion; between 111 and 1396 to 16 hours after ingestion; and up to 1935 to 24 hours after ingestion; wherein AUCcumha units of (quetiapine in nanograms) x hour / milliliter.

In some embodiments of the invention, a solid dosage form comprises 200 mg of que-thiapine, the dosage form, after ingestion under steady-state conditions by different humans, resulting in distinct time-dependent concentrations of quetiapine in blood plasma, which have a cumulative area under the curve, AUC-CUm, which is: up to 177 to one hour after ingestion; between 35 and 1318 to 4 hours after ingestion; between 188 and 3115 to 8 hours after ingestion; between 251 and 4650 at 12 hours after ingestion; between 362 and 5666 at 16 hours after ingestion; and between 441 and 6899 to 24 hours after ingestion; wherein AUCCUmha units of (quetiapine in nanograms) x hour / milliliter.

In some embodiments of the invention, a solid dosage form comprises 400 mg of quetiapine, the dosage form, after ingestion under steady-state conditions by different humans, resulting in distinct time-dependent concentrations of quetiapine in the blood plasma, which have a cumulative area under the curve, AUC-CUm, which is between: 3 and 320 at one hour after ingestion; between 143 and 2667 at 4 hours after ingestion; between 575 and 5158 to 8 hours after ingestion; between 916 and 8722 at 12 hours after ingestion; between 1037 and 10685 at 16 hours after ingestion; and between 1031 and 13033 to 24 hours after ingestion; wherein AUCcumha units of (quetiapine in nanograms) x hour / milliliter.

In some embodiments of the invention, a formulation comprises quetiapine fumarate and 30.0% hydroxy propyl methyl cellulose, wherein 15-29 of 30.0% is a first constituent of hydroxy propyl methyl cellulose, such that the formulation satisfies a predetermined dissolution criterion; the remaining 30.0% is a second constituent of hydroxypropyl methyl cellulose; the first and second constituents correspond, respectively, to a first gradation of hydroxy propyl methyl cellulose which has an apparent viscosity between 80 cp and 120 cp and a second hydroxy propyl methyl cellulose which has an apparent viscosity between 3000 cp and 5600 cp cp.

In some embodiments, the formulation comprises 11-12 wt% quetiapine fumarate. In some embodiments, the formulation comprises 29.5-30.5% by weight of quetiapine fumarate. In some embodiments, the formulation comprises 37.9-38.9% by weight of quetiapine fumarate. In some embodiments, the formulation comprises 52.4-53.4% by weight of quetiapine fumarate.

In some embodiments, the formulation comprises quetiapine or a pharmaceutically acceptable salt thereof in which the quetiapine content is from about 9.6% to about 10.4% by weight and where the formula comprises about 30% hydroxy propyl methyl cellulose. % by weight and 7.2% by weight sodium citrate dihydrate.

In some embodiments, the formulation comprises quetiapine or a pharmaceutically acceptable salt thereof in which the quetiapine content is from about 25.6% to about 26.5% by weight and where the dosage form comprises about 30% hydroxy propyl methyl cellulose. % by weight and sodium citrate dihydrate at about 12.5% by weight.

In some embodiments, the formulation comprises quetiapine or a pharmaceutically acceptable salt thereof in which the quetiapine content is from about 32.9% to about 33.8% by weight and wherein the dosage form comprises sodium citrate dihydrate at about 12.5% by weight and hydroxy propyl methyl cellulose at about 30% by weight.

In some embodiments, the formulation comprises quetiapine or a pharmaceutically acceptable salt thereof in which the quetiapine content is from about 37.1% to about 38.0% by weight and wherein the dosage form comprises 12.5% sodium citrate dihydrate. by weight and about 30 weight percent hydroxy propyl methyl cellulose and wherein about 15 to about 30 weight percent of the hydroxy propyl methyl cellulose is a first constituent of hydroxy propyl methyl cellulose; the 30% remaining is a second constituent of hydroxy pro-pil methyl cellulose; and the first and second constituents correspond, respectively, to a first gradation of hydroxy propyl methyl cellulose which has an apparent viscosity between about 80 cp and about 120 cp and a second hydroxy propyl methyl cellulose which has an apparent viscosity between about 3000 cp and about 5600 cp, wherein the ratio of the first gradation of hydroxy propyl methyl cellulose to the second gradation of hydroxy propyl methyl cellulose is not from 25.0 to 5.0.

In some embodiments, the formulation comprises quetiapine or a pharmaceutically acceptable salt thereof in which the quetiapine content is from about 45.5% to about 46.4% by weight and wherein the dosage form comprises sodium citrate dihydrate a about 11.5% by weight and hydroxy propyl methyl cellulose at about 30% by weight.

In some embodiments, the invention comprises a method for effectively treating psychiatric disorders in humans, comprising administering orally to a human patient on a once-daily basis of an oral dosage form. sustained release containing quetiapine or a pharmaceutically acceptable salt thereof in which the quetiapine content is 50 mg which at steady state provides a time to the maximum plasma concentration (tmax) of the antipsychotic in about 2 to about 16 hours, a maximum plasma concentration (Cmax) which is greater than or equal to four times the plasma concentration of the said antipsychotic at approximately 24 hours and which dosage form provides effective treatment of psychosis for approximately 24 hours or more after administration to the patient.

In some embodiments, the invention comprises a method for effectively treating psychosis in humans, comprising administering orally to a human patient on a once-daily basis of a dosage form. prolonged release hour which contains quetiapine or a pharmaceutically acceptable salt thereof in which the quetiapine content is 150 mg which at steady state provides a time to the maximum concentration in the plasma (tmax) of the antipsychotic said in about 2 at approximately 16 hours, a maximum plasma concentration (Cmax) which is greater than or equal to four times the plasma concentration of the antipsychotic at approximately 24 hours and which dosage form provides effective treatment psychosis for approximately 24 hours or more after administration to the patient.

In some embodiments, the invention comprises a method for effectively treating psychiatric disorders in humans, comprising oral administration to a human patient on a once daily basis of an oral sustained release dosage form. which contains quetiapine or a pharmaceutically acceptable salt thereof in which the quetiapine content is 200 mg which at steady state provides a time to the maximum concentration in plasma (tmax) of the antipsychotic in from about 2 to about 8 hours, a concentration plasma maximum (Cmax) which is greater than or equal to four times the plasma concentration of the antipsychotic said at approximately 24 hours and which dosage form provides effective treatment of psychosis for approximately 24 hours or more after administration patient administration.

In some embodiments, the invention comprises a method for effectively treating psychiatric disorders in humans, comprising administering orally to a human patient on a once-daily basis of an oral dosage form. prolonged release containing quetiapine or a pharmaceutically acceptable salt thereof in which the quetiapine content is 400 mg which at steady state provides a time to maximum plasma concentration (tmax) of the antipsychotic in about 3 to about 8 hours, a maximum plasma concentration (Cmax) which is greater than or equal to four times the plasma concentration of the said antipsychotic at approximately 24 hours and an area under the curve between the time of administration and 24 hours after administration (AUCGUm, 24) which is greater than or equal to about 6000 ng.hour / ml and which dosage form provides effective treatment of psychosis for about 24 hours or more after administration to the patient.

In some embodiments, when the dissolution of the formulation occurs in a basket apparatus which has a rotational speed of 200 revolutions per minute and which contains 900 milliliters of 0.05 molar sodium citrate and 0.09 normal sodium hydroxide to which 100 milliters of 0.05 molar sodium phosphate and 0.46 normal sodium hydroxide are added after 5 hours: not more than 20% of the quetiapine is dissolved during the first one hour period of dissolution. In some embodiments, 47-69% of the quetiapine is dissolved during the first six hour period of dissolution. In some embodiments, 65-95% of the quetiapine is dissolved during the first 12 hour period of dissolution. In some embodiments, at least 85% of the quetiapine is dissolved during the first 20 hour period of dissolution.

In some embodiments of the invention, a formulation comprises quetiapine fumarate and 30.0% hydroxy propyl methyl cellulose, wherein 15-29 of 30.0% is a first constituent of hydroxy propyl methyl cellulose, such that the formulation at least one dissolution target excellently exhibits; the remaining 30.0% is a second constituent of hydroxy propyl methyl cellulose; the first and second constituents correspond, respectively, to a first gradation of hydroxy propyl methyl cellulose which has an apparent viscosity between 80 cp and 120 cp and a second hydroxy propyl methyl cellulose which has an apparent viscosity between 3000 cp and 5600 cp.

In some embodiments, the formula comprises 11-12% by weight of quetia-pine fumarate. In some embodiments, the formulation comprises 29.5-30.5% by weight of quetiapi-na fumarate. In some embodiments, the formulation comprises 37.9-38.9% by weight of quetiapi-na fumarate. In some embodiments, the formulation comprises 52.4-53.4% by weight of quetiapi-na fumarate.

In some embodiments, a first objective is, when dissolution occurs in a basket apparatus which has a rotational speed of 200 revolutions per minute and which comprises 900 milliliters of 0.05 molar sodium citrate and sodium hydroxide. 0.09 normal sodium, to which 100 milliliters of 0.05 molar sodium phosphate and 0.46 normal sodium hydroxide were added after 5 hours: 58% of the quetiapine is dissolved in the first six hour period of dissolution. In some embodiments, a second target is: 80% of the quetiapine is dissolved in the first 12 hour period of dissolution.

In some embodiments of the invention, a solid dosage form comprises a dose of que-thiapine, the dosage form, after ingestion under steady-state conditions by different humans, resulting in dependent concentrations. the blood plasma quetiapine time, the mean of which has a dose-regulated concentration, C / dose, which is between: about 0.433 and about 0.678 at one hour after administration; about 1.01 and about 1.35 at 4 hours after administration; about 0.930 and about 1.35 at 8 hours after administration; about 0.590 and about 1.07 at 12 hours after administration; and about 0.204 and about 1.22 at 16 hours after administration; where the dose is between 49.5 mg and 249.5 mg and C is expressed in nanograms of quetiapine per milliliter of plasma.

In some embodiments of the invention, a solid dosage form comprises a dose of que-thiapine, the dosage form, after ingestion under steady-state conditions by different humans, resulting in dependent concentrations. the blood plasma quetiapine time, the mean of which has a dose-regulated concentration, C / dose, which is between: about 0.433 and about 0.678 at one hour after administration; about 1.01 and about 1.35 at 4 hours after administration; about 0.930 and about 1.35 at 8 hours after administration; about 0.590 and about 1.07 at 12 hours after administration; and about 0.204 and about 1.22 at 16 hours after administration; where the dose is greater than 350 mg and and C is expressed in nanograms of quetiapine per milliliter of plasma.

In some embodiments of the invention, a solid dosage form comprises an amount of quetiapine and 30% of hydroxy propyl methyl cellulose and of, wherein 15-29 of 30.0% is a first constituent of hydroxy propyl methyl cellulose, in a manner such that the formulation excellently exhibits the time-dependent ratio Crdose; the remaining 30.0% is a second constituent of hydroxy propyl methyl cellulose; the first and second constituents correspond, respectively, to a first gradation of hydroxy propyl methyl cellulose which has an apparent viscosity between 80 cp and 120 cp and a second hydroxy propyl methyl cellulose which has an apparent viscosity between 3000 cp and 5600 of the Criminal Code; and Crdose is within a range defined by

where: C is the mean blood plasma concentration of quetiapine, in nanograms of quetiapine per milliliter of plasma, at time t after administration of quetiapine to a human; the base is included between 0.1227 and 0.2428; Ke is included between 0.2344 and 0.2678; Kaè between, inclusive, 0.1396 and 0.1592; and the dose is between 49.5 mg and 249.5 mg.

In some embodiments of the invention, a solid dosage form comprises an amount of quetiapine and 30% hydroxy propyl methyl cellulose and, wherein 15-29 of 30.0% is a first constituent of hydroxy propyl methyl cellulose, such as that the formulation excellently exhibits the time-dependent ratio Crdose; the remaining 30.0% is a second constituent of hydroxy propyl methyl cellulose; the first and second constituents correspond, respectively, to a first gradation of hydroxy propyl methyl cellulose which has an apparent viscosity between 80 cp and 120 cp and a second hydroxy propyl methyl cellulose which has an apparent viscosity between 3000 cp and 5600 of the Criminal Code; and Crdose is within a range defined by

where: C is the mean blood plasma concentration of quetiapine, in nanograms of quetiapine per milliliter of plasma, at time t after administration of quetiapine to a human; the base is between, not included, 0.1227 and 0.2428; Ke is between, inclusive, 0.2344 and 0.2678; Kaè between, inclusive, 0.1396 and 0.1592; and the dose is greater than 350 mg.

The invention may include a process for producing a solid dose form which has a composition that includes an active ingredient and a first and second constituent. The active ingredient can be quetiapine. In some embodiments of the invention, the method may comprise entering a multivariate model of first data corresponding to a first constituent; entry into the model of second data corresponding to a second constituent; use of the model, identification of a relationship between an amount of one constituent and an amount of a second constituent in such a way that the dosage form satisfies a dissolution criterion when the composition includes the first and second constituents in proportion to the report. This procedure can be used, for example, to find a constituent ratio to obtain a desired dissolution profile in the face of variations in constituent properties, such as lot-to-lot or source-to-source variations, which may occur during manufacture of the dosage form, such as commercial scale manufacturing over an extended period of time, such as when batches of identical constituents may not be readily available.

In some embodiments, the first and second constituents comprise the first and second batches of hydroxy propyl methyl cellulose, respectively. In some embodiments, the first and second batches have first and second viscosity, respectively, and the first viscosity is different from the second viscosity. In some embodiments, the first viscosity is in the range of 80-120 cp and the second viscosity is in the range 3000-5600 cp.

In some embodiments, the first and second data include the measured viscosities which correspond to the first and second batches, respectively. In some embodiments, the first and second data comprise the hydroxypropoxy contents of the first and second batches, respectively. In some embodiments, at least one of the hydroxy propoxy contents is measured using nuclear magnetic resonance. In some embodiments, at least one of the methoxy contents is measured using nuclear magnetic resonance.

In some embodiments, the first and second data include the weight average molecular weights (hereinafter, "molecular weight" or "molecular weights", as suitable) corresponding to the first and second batches, respectively.

In some embodiments, the first and second data comprise the methoxy content of the first and second batches, respectively.

In some embodiments, the first and second data include particle size information corresponding to the first and second batches, respectively. Particle size information can be characterized as, for example,% -through-100-mesh (an index that can be taken from the supplier's certificate of analysis; the smallest "mesh" sieve size 3 1/2 to 400 are indicated by the number of openings per linear inch in the sieve. Thus, a 100 mesh sieve has 100 openings per inch. For example, a 100 mesh sieve may have holes that are 149 x 149 microns.% Through a 100 mesh sieve is therefore the weight percentage of particles that are less than 149 microns in diameter.) The particle size can also be characterized as the average particle diameter (D50). and / or particle size amplitude, both of which can be determined using a laser diffraction technique.

In some embodiments, the first and second data include information on the number average molecular weight (hereinafter, "molecular number") that corresponds to the first and second batches, respectively.

In some embodiments, the method comprises inputting into the model the content of the quetiapine salt that corresponds to the composition.

In some embodiments, the method comprises inputting into the model a content of an excipient corresponding to the composition.

In some embodiments, the method includes inputting the weight of the dosage form into the model.

In some embodiments, the method comprises inputting into the model the amount of quetiapine that corresponds to the composition; in which the first and second data include, with respect to the first and second batches, respectively: contents of hydroxy propoxy; and information on the molecular weight. In some embodiments, the hydroxy propoxy contents are characterized as percentages by weight of a total weight of hydroxy propyl methyl cellulose.

In some embodiments, the ratio of the first to the second component has: a minimum value of 15% by weight of the composition in 15%: 15% by weight of the composition; and a maximum value of 29% by weight of the composition: 1% by weight of the composition.

In some embodiments, the dissolution criterion is met when the formulation in a solid dosage form, when subjected to predetermined conditions for a certain time, dissolves to an extent that is within a predetermined range. In some embodiments, the dissolution criterion is met when the measurement is optimal within the range.

In some embodiments, when the ratio is a first ratio, the utilization of the model includes the prediction of dissolution for a second ratio; and the dissolution measure is optimal when the measure is closer to the center of the interval than is the dissolution which corresponds to the second ratio.

The invention may include a process for producing the dosage form by establishing the first and second properties of the first and second constituents, respectively, a correlation between a ratio and dissolution profile information; wherein the ratio is between the amount of a first constituent and the amount of a second constituent in such a way that the dosage form satisfies a dissolution criterion when the composition includes the first and second constituents in proportion to the report.

In some embodiments, the first property promotes dissolution; and the second property delays dissolution. In some embodiments, the first property corresponds to the hydroxy propoxy content.

In some embodiments, the second property corresponds to viscosity, molecular weight, or molecular number.

In some embodiments, the first property corresponds to the hydroxy propoxy content and the second property corresponds to the viscosity.

In some embodiments, the dissolution profile information includes a first value which corresponds to a time and a second value which corresponds to the measure of dissolution over time.

In some embodiments, the correlation can be realized in a multivariate model.

The method may include the measurement of hydroxy propoxy and methoxy of a plurality of batches of hydroxy propyl methyl cellulose. In some embodiments the measurement is made using nuclear magnetic resonance (NMR). A first gradation of hypromellose has a first viscosity and a second gradation can have a second viscosity. The process may include input into a multivariate model of the strength of the tablet and the hydroxypropoxy content and molecular weight of each of the first and second strengths. The method may also include inputting into the model a series of ratios between an amount of the first gradation and an amount of the second gradation. The method may also include identifying, using the model, an optimal ratio that corresponds to an expected dissolving profile that has a smaller deviation from an objective profile than the deviation obtained using the other ratios. Alternatively, the method may include identifying, using the model, at least one ratio that produces a formulation that satisfies a desired dissolution profile.

In some embodiments, the model may be an artificial neural network ("ANN") model.

In some embodiments, the correlation can be realized in a look-up table (data structure to replace computation operations).

Summary Description of the Figures

The foregoing and other features of the present invention, its nature and various advantages will be most apparent upon consideration of the following detailed description, taken in conjunction with the accompanying illustrations and in which:

Figure 1 is a schematic diagram showing the chemical structures which can be used in accordance with the principles of the invention.

Figure 2 is a flow chart showing a manufacturing process which can be used in accordance with the principles of the invention.

Figure 3 is a graph showing clinical data based on a formulation in accordance with the principles of the invention.

Figure 4 is a graph showing clinical data based on a formulation in accordance with the principles of the invention.

Figure 5 is a graph showing clinical data based on a formulation which can be obtained using the methods in accordance with the principles of the invention.

Figure 6 is a graph showing clinical data based on a formulation in accordance with the principles of the invention.

Figure 7 is a graph showing clinical data normalized by Figures 3-6.

Figure 8 is a graph showing the effect of different factors on a property of a formulation in accordance with the principles of the invention.

Figure 9 is a graph showing a correlation between a chemical attribute of the polymer and a characteristic of the polymer.

Figure 10 is a graph showing a correlation between a physical attribute of the polymer and a characteristic of the polymer.

Figure 11 is a graph showing in vitro dissolution data based on formulations in accordance with the principles of the invention.

Figure 12 is a graph showing a feature of a gelling agent which can be used in accordance with the principles of the invention.

Figure 13 is a graph showing the release of hypromellose for different grades of hypromellose which can be used in accordance with the principles of the invention.

Figure 14 is a graph showing the release of hypromellose and a medicament which can be used in accordance with the principles of the invention.

Figure 15 is a schematic diagram showing the architecture of a multivariate model which can be used in accordance with the principles of the invention.

Figure 16 is a schematic diagram of a multi-variable model according to the principles of the invention.

Figure 17 is a graph showing predictive data and acceptance criteria in accordance with the principles of the invention.

Figure 18 is a flow chart showing a method of using the model of Figure 15.

Figure 19 is a flow chart showing a method of using the model of Figure 15.

Figure 20 is an illustrative data table in accordance with the principles of the invention.

Figure 21 is a graph of in vitro dissolution data based on a formulation in accordance with the principles of the invention.

Figure 22 is a graph of in vitro dissolution data based on a formulation in accordance with the principles of the invention.

Figure 23 is a graph of in vitro dissolution data based on a formulation in accordance with the principles of the invention.

Figure 24 is a graph of in vitro dissolution data based on a formulation in accordance with the principles of the invention.

Figure 25 is a graph of in vitro dissolution data based on a formulation in accordance with the principles of the invention.

Detailed Description of the Embodiments Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as those commonly understood by persons with normal experience in the art to which this invention belongs. While similar or equivalent methods and materials to those disclosed herein may be used in the practice or test of the present invention, suitable methods and materials are disclosed hereinafter. The materials, procedures and examples are illustrative only and are not intended to be limiting. All publications, patents and other documents mentioned herein are incorporated by reference in their entirety.

In order to further define the invention, the following terms and definitions are provided here.

The term "treat" or "treatment" is intended to include but is not limited to the alleviation or alleviation of symptoms such as psychotic disorders or hyperactivity in a mammal such as a human.

The term "patient" refers to an animal including a mammal (e.g., a human).

The term "bioavailability" includes but is not limited by reference to the rate and extent to which an active ingredient or active moiety is absorbed by a medicament product and becomes available at the site of action.

The term "Prolonged Release" includes but is not limited to referring to products which are formulated to make the medicament available during an extended period after administration.

A formulation may include a hydrophilic matrix comprising a gelling agent, 11- [4 [2 (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine, or a pharmaceutically salt thereof. acceptable, such as a hemifumarate salt and one or more pharmaceutically acceptable excipients.

Examples of the gelling agents which may be present in embodiments of the invention include such substances as hydroxy propyl cellulose, hydroxy methyl cellulose, hydroxy ethyl cellulose, hydroxy propyl ethyl cellulose, methyl cellulose, carboxy ethyl cellulose, hydroxy ethyl cellulose, carboxymethyl hydroxy ethyl cellulose, carbomer, sodium carboxy methyl cellulose, polyvinyl pyrrolidone and the like, or mixtures thereof. In certain embodiments, the gelling agent may comprise hypromellose.

The amount of gelling agent, in combination with the quetiapine and any excipient, can be selected such that the active ingredient is released from the formulation in a controlled manner, over a period of approximately 24 hours.

The gelling agent may be present in a range of about 5 to 50% (by weight). The range can be about 5 to 40%. The range can be approximately 8 to 35%. The range can be about 10 to 35%. The range can be 10 to 30%. The range can be 15 to 30%. (Percentages by weight, as used herein, are relative to the weight of the tablets with a core, excluding the weight of each coating, unless otherwise specified.) Some embodiments of the invention may include hypromellose mixtures. which include more than one grade of polymers. The polymers are commercially available under several commercial names, for example METHOCEL® E, F, J and K from the Dow Chemical Company, U.S.A. and METOLOSE ™ 60SH, 65SH and 90SH from Shin-Etsu, Ltd., Japan. The grades have differences in hydroxy propoxy and methoxy content as well as viscosity and other characteristics. Different batches of hypromellose, even of the same gradation, can have differences in the contents of hydroxy propoxy and methoxy, in viscosity and in other characteristics.

The formulation may contain a buffer or a pH modifying agent, for example if the active ingredient exhibits pH dependent solubility, as is the case for quetiapine salts such as quetiapine fumarate.

The formulation will generally contain one or more excipients. Such excipients may include diluents such as lactose, microcrystalline cellulose, dextrose, mannitol, sucrose, sorbitol, gelatin, acacia, dicalcium phosphate, tricalcium phosphate, monocalcium phosphate, sodium phosphate, sodium carbonate and the like, preferably lactose. and microcrystalline cellulose; lubricants such as stearic acid, zinc, magnesium or calcium stearate and the like, preferably magnesium stearate; binders such as sucrose, polyethylene glycol, povidone (polyvinyl pyrrolidone), ce-royal starch or corn starch, pregelatinised starch and the like; dyes such as ferric oxides, FD & C dyes, lacquers and the like; flavoring agents; and pH modifying agents which include suitable organic acids or alkali metal salts thereof (e.g., lithium, sodium or potassium), such as benzoic acid, citric acid, tartaric acid, succinic acid and adipic acid and the like or the corresponding salts of alkali metal, preferably the alkali metal salts of such acids and in particular the sodium salt of citric acid (i.e. sodium citrate). As is well known, some excipients have multiple functions, such as being both diluents and binders.

In some embodiments of the invention, the formulation may be present in a solid dosage form such as a tablet, caplet or any other suitable form comprising 11— [4— [2— (2— hydroxyethoxy) ethyl] -1 -piperazinyl] dibenzo [b, f]

[1,4] thiazepine hemifumarate ("quetiapine fumerate"), 6 to 18 wt% sodium citrate dihydrate, 30.0 wt% hydroxy propyl methyl cellulose, wherein 15-29 of 30.0% is a first constituent of hydroxy propyl methyl cellulose; the remainder of 30.0% is a second constituent of hydroxy propyl methyl cellulose; and the first and second constituents correspond, respectively, to a first gradation of hydroxy propyl methyl cellulose which has "a apparent viscosity, between 80 centipoise ("cp") and 120 cp and a second hydroxy propyl methyl cellulose which has an apparent viscosity between 3000 cp and 5600 cp. The tablet may comprise 11-12% by weight of 11- [4- [2- (2-hydroxy ethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate. The tablet may comprise 29.5-30.5% by weight of 11— [4— [2- ( 2-hydroxy ethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate. The tablet may comprise 37.9-38.9% by weight of 11- [4- [2- (2- hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate. In some embodiments, the paste comprises 52.4-53.4% by weight of 11— [4— [2— (2— hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f]

[1,4] thiazepine hemifumarate.

In some embodiments, the viscosities of the formulation are consistent with the apparent viscosities of the Ubbelohde viscometer of 2 wt.% Hydroxy propyl methyl cellulose in water at 20 °, as determined using the method described in The United States Pharmacopoeia ( USP30-NF25), United States Pharmacopoeia Convention, Ine. 2007, page 2323 which is incorporated herein by reference.

In some embodiments of the invention, the formulation comprises sodium citrate dihydrate present in about 7.2-12.5% by weight. In some embodiments, the formulation comprises sodium citrate dihydrate present at 7.2% by weight. In some embodiments, the formulation comprises sodium citrate dihydrate present at 11.5% by weight. In some embodiments, the formulation comprises sodium citrate dihydrate present at 12.5% by weight.

In some embodiments of the invention, the formulation comprises lactose monohydrate present up to a maximum of about 30% by weight. In some embodiments, the formulation comprises lactose monohydrate present in 25.1% by weight. In some embodiments, the formulation comprises lactose monohydrate present in 13.0% by weight. In some embodiments, the formulation comprises lactose monohydrate present in 8.8% by weight. In some embodiments, the formulation comprises lactose monohydrate present in 1.8% by weight.

In some embodiments, the formulation comprises microcrystalline cellulose present up to about 30% by weight. In some embodiments, the formulation comprises microcrystalline cellulose present in 25.1% by weight. In some embodiments, the formulation comprises microcrystalline cellulose present in 13.0% by weight. In some embodiments, the formulation comprises the microcrystalline cell present in 8.8% by weight. In some embodiments, the formulation comprises microcrystalline cellulose present in 1.8% by weight.

In some embodiments, the tablet comprises an amount of magnesium stearate about 1% to 3% by weight. In some embodiments, the tablet comprises magnesium stearate present in 1.0% by weight. In some embodiments, the paste comprises magnesium stearate present in 1.5% by weight. In some embodiments, the paste comprises magnesium stearate present in 2.0% by weight.

In some embodiments, hydroxy propyl methyl cellulose comprises 9.8 to 13.4 wt% hydroxy propyl methyl cellulose, as measured by nuclear magnetic resonance ("NMR"), hydroxy propoxy. In some embodiments, hydroxy propyl me -thyl cellulose comprises 26.4 to 29.2% by weight of the hydroxy propyl methyl cellulose, as measured by NMR, methoxy.

In some embodiments of the invention the solid dosage form comprises 50 milligrams ("mg") of quetiapine, for example in a total core mass of 500 mg. In some embodiments, the solid dosage form comprises 150 mg of quetiapine, for example, in a total core mass of 575 mg. In some embodiments, the solid dosage form comprises 200 mg of quetiapine, e.g. in a total core mass. of 600 mg. In some embodiments, the solid dosage form comprises 400 mg of quetia-pine, for example in a total core mass of 870 mg.

In some embodiments of the invention, the formulation is present in a solid dosage form comprising 50 mg of quetiapine, the dosage form, after ingestion under steady state conditions by a human, resulting in a concentration in the blood plasma, in nanograms, of quetiapine per milliliter of plasma, which is up to about: 67.6 at one hour after ingestion; 124 to 4 hours after ingestion; 105 to 8 hours after ingestion; 74.3 to 12 hours after ingestion; and 236 to 16 hours after ingestion.

In some embodiments of the invention the formulation is a solid dosage form comprising 200 mg of quetiapine, the dosage form, after ingestion under steady-state conditions by a human, resulting in a concentration in the blood plasma, in nanograms of quetiapine per milliliter of plasma, that is: up to about 251 to one hour after ingestion; between about 32.2 and about 416 to 4 hours after ingestion; up to a maximum of approximately 496 to 8 hours after ingestion; between about 4.6 and about 323 to 12 hours after ingestion; and up to a maximum of approximately 251 to 16 hours after ingestion.

In some embodiments of the invention, the formulation is a solid dosage form comprising 400 mg of quetiapine, the dosage form, after ingestion under steady-state conditions by a human, resulting in a concentration in blood plasma, in nanograms of quetiapine per milliliter of plasma, which is: between about 15.9 and about 391 at one hour after ingestion; until about 1052 to 4 hours after ingestion; between about 63.1 and about 785 to 8 hours after ingestion; between about 11.1 and about 613 to 12 hours after ingestion; and up to a maximum of approximately 448 to 16 hours after ingestion.

In some embodiments of the invention, a dosage form comprises: 30.0% by weight of hydroxy propyl methyl cellulose and 7.2% of sodium citrate dihydrate. In certain embodiments, 15-29 of 30.0% is a first constituent of hydroxy pro-pyl methyl cellulose; the remainder of 30.0% is a second constituent of hydroxy propyl methyl cellulose; and the first and second constituents correspond, respectively, to a first gradation of hydroxy propyl methyl cellulose which has an apparent viscosity between 80 cp and 120 cp and a second hydroxy propyl methyl cell which has an apparent viscosity between 3000 cp and 5600 cp. In some embodiments, the viscosities of the dosage form are consistent with the relative viscosities of the Ubbelohde viscometer of 2 wt.% Hydroxy propyl methyl cellulose in water at 20 DEG, as determined using the method described in The United States Pharmacopoeia (USP30-NF25), United States Pharmacopoeia Convention, Ine. 2007, page 2323. In some embodiments, the first and second constituents, respectively, have viscosities of 80-120 cp and 3000-5600 cp.

In some embodiments of the invention a solid dosage form comprises 50 mg of quetia-pine, the dosage form, after ingestion under steady-state conditions by a human, resulting in a dependent concentration. from the time of quetiapine in the blood plasma, in quetiapine in nanograms per milliliter of plasma, having a maximum value, Cmax, which is up to about 239 and corresponds to a time tmax which is between 2 and 16 hours after ingestion. In some embodiments, the concentration has a value of C24, which is up to about 39.2 and corresponds to a time t24, 24 hours after ingestion; and the ratio Cmax: C24 is up to about 35.2.

In some embodiments of the invention, a solid dosage form comprises 200 mg of que-thiapine, the dosage form, after ingestion under steady-state conditions by a human, resulting in a concentration-dependent concentration. quetiapine time in blood plasma, in que-thiapine in nanograms per milliliter of plasma, having a maximum value, Cmax, which is between about 3.9 and about 601 and corresponds to a time tmax which is between 2 and 8 hours after ingestion. In some embodiments, the concentration has a value of C24, which is up to about 156 and corresponds to a time t24, 24 hours after ingestion; and the ratio Cmax: C24 is up to about 20.9.

In some embodiments of the invention, a solid dosage form comprises 400 mg of quetiapine, the dosage form, after ingestion under steady-state conditions by a human, resulting in a time-dependent concentration of quetiapine in blood plasma, in quetiapine in nanograms per milliliter of plasma, having a maximum value, Cmax, which is between about 80 and about 1109 and corresponds to a time tmax which is between 3 and 8 hours after ingestion. In some embodiments, the concentration has a value of C24, which is up to about 265 and corresponds to a time t24, 24 hours after ingestion; and the ratio Cmax: C24 is up to about 25.9.

In some embodiments of the invention, a solid dosage form comprises 50 mg of quetia-pine, the dosage form, after ingestion under steady-state conditions by different humans, resulting in distinct concentrations dependent on from the time of quetiapine in the blood plasma, which have a maximum value, C mean max / between about 5.1 and about 117 nanograms of quetiapine per milliliter of plasma, C mean max corresponding to a time that is between 2.5 and 3.5 hours after the ingestion. In some embodiments, the distinct concentrations have an average value C, 24 which is about 14.8 and corresponds to a time of 24 hours after ingestion; and the ratio Cmedia max: Cmedia, 24 is about 4.1.

In some embodiments of the invention, a solid dosage form comprises 200 mg of quetiapine, the dosage form, after ingestion under steady-state conditions by different humans, resulting in distinct time-dependent concentrations of quetiapine in the blood plasma, which have a maximum value, C average but x r which is up to about 550.4 nanograms of quetiapine per milliliter of plasma, C average max / corresponding to a time that is between 5.5 and 6.5 hours after ingestion. In some forms of alization, the distinct concentrations have an average C average value, 24 which is about 64.9 and corresponds to a time of 24 hours after ingestion; and the Cmedia report

maxCmedia, 24C About 4.0.

In some embodiments of the invention, a solid dosage form comprises 400 mg of que-thiapine, the dosage form, after ingestion under steady-state conditions by different humans, resulting in distinct time-dependent concentrations of quetiapine in blood plasma, which have a maximum value, C average max / which is up to about 1062 nanograms of quetiapine per milliliter of plasma, C average max (corresponding to a time that is between 2.5 and 3.5 hours after ingestion. some forms of realization, the distinct concentrations have an average value C average, 24 which is about 114 and corresponds to a time of 24 hours after ingestion; and the ratio Cmediamax · Cmedia, 24C about 4. 6.

In some embodiments of the invention, a solid dosage form comprises 50 mg of quetia-pine, the dosage form, after ingestion under steady-state conditions by different humans, resulting in distinct concentrations dependent on teeth from the time of quetiapine in the blood plasma, which have a cumulative area under the curve, AUCCUmxwhich is: up to 46 to one hour after ingestion; between 8 and 352 to 4 hours after ingestion; between 34 and 789 to 8 hours after ingestion; between 83 and 1092 to 12 hours after ingestion; between 111 and 1396 to 16 hours after ingestion; and up to 1935 to 24 hours after ingestion; wherein AUCCUmha units of (quetiapine in nanograiranes) x hour / milliliter.

In some embodiments of the invention, a solid dosage form comprises 200 mg of que-thiapine, the dosage form, after ingestion under steady-state conditions by different humans, resulting in distinct time-dependent concentrations of quetiapine in blood plasma, which have a cumulative area under the curve, AUC-cum, which is: up to 177 to one hour after ingestion; between 35 and 1318 to 4 hours after ingestion; between 188 and 3115 to 8 hours after ingestion; between 251 and 4650 at 12 hours after ingestion; between 362 and 5666 at 16 hours after ingestion; and between 441 and 6899 to 24 hours after ingestion; wherein AUCCUmha units of (quetiapine in nanograms) x hour / milliliter.

In some embodiments of the invention, a solid dosage form comprises 400 mg of que-thiapine, the dosage form, after ingestion under steady-state conditions by different humans, resulting in distinct time-dependent concentrations of quetiapine in blood plasma, which have a cumulative area under the curve, AUC-CUm, which is between: 3 and 320 at one hour after ingestion; between 143 and 2667 at 4 hours after ingestion; between 575 and 6158 to 8 hours after ingestion; between 916 and 8722 at 12 hours after ingestion; between 1037 and 10685 at 16 hours after ingestion; and between 1031 and 13033 to 24 hours after ingestion; wherein AUCCUmha units of (quetiapine in nanograms) x hour / milliliter.

In some embodiments of the invention, a formulation comprises quetiapine fumarate and 30.0% hydroxy propyl methyl cellulose, wherein 15-29 of 30.0% is a first constituent of hydroxy propyl methyl cellulose, such that the formulation satisfies a predetermined dissolution criterion; the remaining 30.0% is a second constituent of hydroxypropyl methyl cellulose; the first and second constituents correspond, respectively, to a first gradation of hydroxy propyl methyl cellulose which has an apparent viscosity between 80 cp and 120 cp and a second hydroxy propyl methyl cellulose which has an apparent viscosity between 3000 cp and 5600 cp cp.

In some embodiments, the formulation comprises 11-12 wt% quetiapine fumarate. In some embodiments, the formulation comprises 29.5-30.5% by weight of quetiapine fumarate. In some embodiments, the formulation comprises 37.9-38.9% by weight of quetiapine fumarate. In some embodiments, the formulation comprises 52.4-53.4% by weight of quetiapine fumarate.

In some embodiments, a first objective is when dissolution occurs in a basket apparatus which has a rotational speed of 200 rpm and which comprises 900 milliliters of 0.05 molar sodium citrate and 0.09 sodium hydroxide. normal, to which 100 milliliters of 0.05 molar sodium phosphate and 0.46 normal sodium hydroxide were added after 5 hours: 58% of the quetiapine is dissolved in the first six hour period of dissolution. In some embodiments, a second target is: 80% of the quetiapine is dissolved in the first 12 hour period of dissolution.

In some embodiments of the invention, a solid dosage form comprises a dose of que-thiapine, the dosage form, after ingestion under steady-state conditions by different humans, resulting in dependent concentrations. the blood plasma quetiapine time, the mean of which has a dose-adjusted concentration C / dose, which is between: about 0.433 and about 0.678 at one hour after administration; about 1.01 and about 1.35 at 4 hours after administration; about 0.930 and about 1.35 at 8 hours after administration; about 0.590 and about 1.07 at 12 hours after administration; and about 0.204 and about 1.22 at 16 hours after administration; where the dose is between 49.5 mg and 249.5 mg and C is expressed in nanograms of quetiapine per milliliter of plasma.

In some embodiments of the invention, a solid dosage form comprises a dose of que-thiapine, the dosage form, after ingestion under steady-state conditions by different humans, resulting in dependent concentrations. the blood plasma quetiapine time, the mean of which has a dose-regulated concentration, C / dose, which is between: about 0.433 and about 0.678 at one hour after administration; about 1.01 and about 1.35 at 4 hours after administration; about 0.930 and about 1.35 at 8 hours after administration; about 0.590 and about 1.07 at 12 hours after administration; and about 0.204 and about 1.22 at 16 hours after administration; where the dose is greater than 350 mg and and C is expressed in nanograms of quetiapine per milliliter of plasma.

In some embodiments of the invention, a solid dosage form comprises an amount of quetiapine and 30% hydroxy propyl methyl cellulose, wherein 15-29 of 30.0% is a first constituent of hydroxy propyl methyl cellulose, so that the formula excellently exhibits the time-dependent ratio Crdose; the remaining 30.0% is a second constituent of hydroxy propyl methyl cellulose; the first and second constituents correspond, respectively, to a first gradation of hydroxy propyl methyl cellulose which has an apparent viscosity between 80 cp and 120 cp and a second hydroxy propyl methyl cellulose which has an apparent viscosity between 3000 cp and 5600 cp ; and Crdose is within a range defined by

where: C is the mean blood plasma concentration of quetiapine, in nanograms of quetiapine per milliliter of plasma, at time t after administration of quetiapine to a human; the base is included between 0.1227 and 0.2428; Ke is included between 0.2344 and 0.2678; Kaè between, inclusive, 0.1396 and 0.1592; and the dose is between 49.5 mg and 249.5 mg.

In some embodiments of the invention, a solid dosage form comprises an amount of quetiapine and 30% hydroxy propyl methyl cellulose, wherein 15-29 of 30.0% is a first constituent of hydroxy propyl methyl cellulose, such as that the formulation excellently exhibits the time-dependent ratio Crdose; the remaining 30.0% is a second constituent of hydroxy propyl methyl cellulose; the first and second constituents correspond, respectively, to a first gradation of hydroxy propyl methyl cellulose which has an apparent viscosity between 80 cp and 120 cp and a second hydroxy propyl methyl cellulose which has an apparent viscosity between 3000 cp and 5600 of the Criminal Code; and Crdose is within a range defined by

where: C is the mean blood plasma concentration of quetiapine, in nanograms of quetiapine per milliliter of plasma, at time t after administration of quetiapine to a human; the base is between, not included, 0.1227 and 0.2428; Ke is between, inclusive, 0.2344 and 0.2678; Kaè between, inclusive, 0.1396 and 0.1592; and the dose is greater than 350 mg.

The invention may include a process for producing a solid dose form which has a composition that includes an active ingredient and a first and second constituent. The active ingredient may be quetiapine. In some embodiments of the invention, the method may comprise entering a multivariate model of first data corresponding to a first constituent; entry into the model of second data corresponding to a second constituent; use of the model, identification of a relationship between an amount of one constituent and an amount of a second constituent in such a way that the dosage form satisfies a dissolution criterion when the composition includes the first and second constituents in proportion to the report. This procedure can be used, for example, to find a constituent ratio to obtain a desired dissolution profile in the face of variations in constituent properties, such as lot-to-lot or source-to-source variations, which may occur during manufacture of the dosage form, such as commercial scale manufacturing over an extended period of time, such as when batches of identical constituents may not be readily available.

In some embodiments, the first and second constituents comprise the first and second batches of hydroxy propyl methyl cellulose, respectively. In some embodiments, the first and second batches have first and second viscosity, respectively, and the first viscosity is different from the second viscosity. In some embodiments, the first viscosity is in the range of 80-120 cp and the second viscosity is in the range 3000-5600 cp.

In some embodiments, the first and second data include the measured viscosities corresponding to the first and second batches, respectively. In some embodiments, the first and second data comprise the hydroxypropoxy contents of the first and second batches, respectively. In some embodiments, at least one of the hydroxy propoxy contents is measured using nuclear magnetic resonance. In some embodiments, at least one of the methoxy contents is measured using nuclear magnetic resonance.

In some embodiments, the first and second data include the weight average molecular weights (hereinafter, "molecular weight" or "molecular weights", as suitable) corresponding to the first and second batches, respectively.

In some embodiments, the first and second data comprise the methoxy content of the first and second batches, respectively.

In some embodiments, the first and second data include particle size information corresponding to the first and second batches, respectively. Particle size information can be characterized as, for example,% -through-100-mesh (an index that can be taken from the supplier's certificate of analysis; the smallest "mesh" sieve size 3 1/2 to 400 are indicated by the number of openings per linear inch in the sieve. Thus, a 100 mesh sieve has 100 openings per inch. For example, a 100 mesh sieve may have holes that are 149 x 149 microns.% Through a 100 mesh sieve is therefore the weight percentage of particles that are less than 149 microns in diameter.) The particle size can also be characterized as the average particle diameter (D50). and / or particle size amplitude, both of which can be determined using a laser diffraction technique.

In some embodiments, the first and second data include information on the number average molecular weight (hereinafter, "molecular number") that corresponds to the first and second batches, respectively.

In some embodiments, the method comprises inputting into the model the content of the quetiapine salt that corresponds to the composition.

In some embodiments, the method comprises inputting into the model a content of an excipient corresponding to the composition.

In some embodiments, the method includes inputting the weight of the dosage form into the model.

In some embodiments, the method comprises inputting into the model the amount of quetiapine that corresponds to the composition; in which the first and second data include, with respect to the first and second batches, respectively: contents of hydroxy propoxy; and information on the molecular weight. In some embodiments, the hydroxy propoxy contents are characterized as percentages by weight of a total weight of hydroxy propyl methyl cellulose.

In some embodiments, the ratio of the first to the second component has: a minimum value of 15% by weight of the composition in 15%: 15% by weight of the composition; and a maximum value of 29% by weight of the composition: 1% by weight of the composition.

In some embodiments, the dissolution criterion is met when the formulation in a solid dosage form, when subjected to predetermined conditions for a certain time, dissolves to an extent that is within a predetermined range. In some embodiments, the dissolution criterion is met when the measurement is optimal within the range.

In some embodiments, when the ratio is a first ratio, the utilization of the model includes the prediction of dissolution for a second ratio; and the dissolution measure is optimal when the measure is closer to the center of the interval than is the dissolution which corresponds to the second ratio.

The invention may include a process for producing the dosage form by establishing the first and second properties of the first and second constituents, respectively, a correlation between a relationship and dissolution profile information; wherein the ratio is between the amount of a first constituent and the amount of a second constituent in such a way that the dosage form satisfies a dissolution criterion when the composition includes the first and second constituents in proportion to the report.

In some embodiments, the first property promotes dissolution; and the second property delays dissolution. In some embodiments, the first property corresponds to the hydroxy propoxy content.

In some embodiments, the second property corresponds to viscosity, molecular weight, or molecular number.

In some embodiments, the first property corresponds to the hydroxy propoxy content and the second property corresponds to the viscosity.

In some embodiments, the dissolution profile information includes a first value which corresponds to a time and a second value which corresponds to the measure of dissolution over time.

In some embodiments, the correlation can be realized in a multivariate model.

The method may include the measurement of hydroxy propoxy and methoxy of a plurality of batches of hydroxy propyl methyl cellulose. In some embodiments the measurement is made using nuclear magnetic resonance (NMR). A first gradation of hypromellose has a first viscosity and a second gradation can have a second viscosity. The process may include input into a multivariate model of the strength of the tablet and the hydroxypropoxy content and molecular weight of each of the first and second strengths. The method may also include inputting into the model a series of ratios between an amount of the first gradation and an amount of the second gradation. The method may also include identifying, using the model, an optimal ratio that corresponds to an expected dissolving profile that has a smaller deviation from an objective profile than the deviation obtained using the other ratios. Alternatively, the method may include identifying, using the model, at least one ratio that produces a formulation that satisfies a desired dissolution profile.

In some embodiments, the model may be an artificial neural network ("ANN") model.

In some embodiments, the correlation can be realized in a look-up table.

Exemplary formulations for the mechanical strengths of the 50 mg, 150 mg, 200 mg, 300 mg and 400 mg tablets are shown in Tables 1-5, respectively.

Table 1

Quetiapine fumarate contains 86.86% by weight quetiapine

Table 2

Quetiapine fumarate contains 86.86% by weight quetiapine

Table 3

Quetiapine fumarate contains 86.86% by weight quetiapine

Table 4

Central part tablet weight 800.00 100.0

Quetiapine fumarate contains 86.86% by weight quetiapine

Table 5

Quetiapine fumarate contains 86.86% by weight quetiapine

Figure 1 shows the substituted anhydroglucose units which make up hypromellose and are involved in the dissolution processes which will be discussed in more detail below in connection with certain exemplary embodiments.

The formulations can be made in 50, 150, 200, 300 and 400 mg sustained release pastes which can be manufactured using one or more of the following devices and processes: standard high shear wet granulation, high shear dryer fluidized bed, grinding, blending, compression, aqueous film coating processes and all other suitable processes which are the same or similar to other manufacturing processes used in the pharmaceutical industry.

The raw materials can be transferred to the high-stress talium granulator and can be mixed for 10 minutes. All excipients (with the exception of magnesium stearate) can be added to the high shear granulator. A suitable mixing time of 10 minutes can be used.

During the wet granulation step water can be added to the dry mix to complete the granulation. There may be a range in both the amount of water added to the granulation and the rate of water addition to provide an acceptable product.

Wet ground material can be dried in a fluidized bed dryer. For the moisture of each batch a loss target of <3% on drying (LOD) can be achieved.

An impact mill can be used for reducing the size of the granulation to provide sufficient compression and flow characteristics.

A 3 minute lubricant mixing time can be used.

Illustrative parameters for tablet processing for two different commercial plants are shown in Table 6.

Table 6

Figure 2 shows an illustrative flow chart for the manufacture of quetiapine fumarate tablets. Manufacturing method 200 may include process flow 210 and processing equipment 250. Process flow may include dry blending and using granulation 212 using the high shear granulator 252, wet grinding 214 using screen mill 254, drying 216 using fluid bed dryer 256, grinding 218 using impact or screen mill 258, blending 220 using diffusion mixer 260, tableting 222 using rotary press 262 and coating 224 using tray coating device 264. Flow 210 and apparatus 250 are merely exemplary and other suitable flow steps as well as processing equipment may be utilized .

In relation to step 253 an exemplary list of the constituents to be mixed dry and granular

wet by means of a high shear granulator 252 is shown. Magnesium stearate 263 can be added through sieve 265 during blending 220. Coating slurry 267 can be included in coating process 224.

The following protocol was used to determine blood plasma concentrations of the active ingredient in patients. Figures 3-6 show the curves of the plasma concentration over time (mean and range).

A multi-center, open-label, multiple-dose study was performed to evaluate the steady-state pharmacokinetics of commercial-scale tablets comprising study formulations ("SF") that have the following quetiapine strengths: 50 mg, 200 mg, 300 mg, and 400 mg. The study formulations have compositions that are shown in Tables 1 to 5. After a two-day wash-out period, patients received oral doses of the study formulations and Immediate Release Medicament ("IR") which is now available under the brand name "Seroquel" (available from AstraZeneca Pharmaceuticals, Wilmington, Delaware) once daily as follows: 50 mg SF per Days 1 - 4, 200 mg SF on Days 5 - 7, 300 mg SF on Days 8 - the, 400 mg SF on Days 12 - 14 and 300 IR on Days 15 - 17. On Days 4 and on, patients consumed a standardized high-fat breakfast within 10 minutes of their scheduled dose data from Day 3 (mg 50; Figure 3), Day 7 (mg 200; Figure 4), Day 10 (mg 300; Figure 5) and Day 14 (mg 400; Figure 6) were used and it was assumed that steady state had been reached for each dose level. In each curve (Figures 3-6), the error bars correspond to a prediction interval of 95%.

The data from the study are reported in Tables 6A and 6B.

In Table 6A, Ct is the concentration, in nanograms per milliliter in the plasma, at a time t, which is expressed in hours after ingestion of the tablet. AUC-cumt is the cumulative area under the concentration curve in (nanograms of quetiapine) x hour / milliliter, at a time t, which is expressed in hours after ingestion of the tablet. The quantities shown in Table 6A that are derived from Cte from AUCCUmt are explained above.

<">" <"> Lower confidence limit for single subject data (2-sided, p = 0.05, n = 12)

<2> Mean for single subject data (n = 12)

<3> Upper confidence limit for single subject data (2-sided, p = 0.05, n = 12)

<4> Minimum, the most frequent and maximum values observed

<5> The maximum value of Cmedia, the mean plasma concentration for all subjects at a single time point

In Table 6B, C / doset is a ratio independent of the concentration resistance, in nanograms of quetiapine per milliliter of plasma, with respect to the resistance of the tablet, in mg of quetiapine, at a time t, which is expressed in hours after the ingestion of the tablet.

Table 6B

The lower confidence limit for C / dose calculated by Cmedia for each resistance for each time point (2-sided, p = 0.05, n = 4)

<2> large Mean (mean of means) of C / dose calculated by C mean for each resistance for each time point (n = 4)

<3> Confidence Limit Limit for C / dose calculated on the same basis as LCL

Each curve (Figures 3-6) also shows a best-fit curve based on a pharmacokinetic model ("PK") using the first-order drug absorption rate and elimination rate constants Kae K, respectively, with the equation

(See, for example, The Tempo Course of Drug Action ,,, by Neubig, R R., in Principles of Drug Action, Pratt, W, B., Ta-ylor, P., (Eds.), 3rd Edition , Churchill Livingstone, Inc. 1990.)

PK model parameters, best-fit values and standard errors ("SE"), together with the 95% confidence interval, for the active ingredient amounts of 50 mg, 200 mg, 300 mg and 400 mg, respectively, are reported in Tables 7-10, which correspond to the data indicated in Figures 3-6, respectively.

Table 7

Table 8

Table 9

Table 10

PK model parameters, best fit values and standard errors (95% confidence interval) for the dose-normalized curve are shown in Table 11, which corresponds to the data indicated in Figure 7. The error bars correspond to the 95% confidence interval.

Table 11

Hypromellose hydrates quickly after ingestion to form a continuous gel layer. The gel layer initially behaves so as to prevent wetting and consequent disintegration of the central part of the tablet, which would lead to the fast and complete release of the drug, then thereafter to mediated release of the medication through a complex mechanism that it involves the internal extension of the hydrated gel layer, swelling, diffusion of the medicament through the gel to the surrounding medium and erosion which causes the release of the active ingredient and hypromellose from the external surface. See "Using Dow Excipients for Controlled Release of Drugs in Hydrophilic Matrix Systems," Technical Guide published by the Dow Chemical Company, September 2006, which is incorporated herein by reference in its entirety.

Hypromellose is a cellulose ether derived by chemical modification of cellulose, a carbohydrate of natural origin which contains a repetitive structure of the anhydroglucose units. Cellulose itself is an insoluble fibrous polymer; however each anhydroglucose unit comprises 5 reactive hydroxyl groups, two of which are used in chain propagation, which leaves three sites for chemical substitution. For pharmaceutical applications, the most commonly used substituents are methyl, ethyl and hydroxy propyl. Ethyl celluloses are insoluble in water but are soluble in certain organic solvents and are useful either alone or in combination with other excipients, such as tablet coatings or in the manufacture of hydrophobic matrix tablets. Methyl celluloses are generally soluble in water, while hydroxypropyl celluloses are soluble both in water and in certain organic solvents. Hypromellose can be substituted by both hydroxypropyl and methyl groups, thereby allowing fine modulation of properties for applications such as use in hydrophilic matrix tablets (see Figure 1).

The concentration of hypromellose is an important consideration in the design of a controlled release hydrophilic matrix tablet. The hypromellose concentration must be high enough to be sure that a continuous gel layer is formed immediately upon exposure to an aqueous medium. Once such a concentration has been exceeded, however, an increase in the hypromellose concentration will lead to a decrease in the release rate due to an increase in the time required for the hypromellose to break the web at the surface of the paste. . At some point the braiding effect will reach a plateau so that a further increase in the hypromellose concentration will not cause further reduction in the rate of drug release. This is because the release of the drug results not only from the erosion of the hypromellose, but also from the diffusion of the solubilized drug within the hydrated matrix. The precise location of the lower concentration threshold and the upper plateau concentration will depend on the characteristics and load of the drug and other excipients, but generally the hypromellose concentration should lie in the range of 20% to 50%.

Hypromellose can be characterized by the following parameters:

Degree of substitution ("DS"). DS refers to the level of substitution in terms of the number of substituted groups of hydroxyl, regardless of the nature of the substituent group, expressed as a mean. For hypromellose, DS is generally redefined to reflect only the substitution of methoxy In both cases the total number of available hydroxyl groups is 3, so that DS lies between 0 and 3, but is more typically between 1.3 and 2.6.

Molar substitution ("MS"). For hypromellose, MS refers to the measure of hydroxypropyl substitution in terms of moles per mole of anhydroglucose and is expressed as an average. Typical values lie in the range 0.2 - 0.4 Since each hydroxypropyl group contains a hydroxyl group, there is no theoretical upper limit for MS.

Wise. The test refers to the content of methoxy (-OCH3) and hydroxypropoxy (-OCH2CHOHCH3), expressed as a percentage.

Chemistry. The chemistry is defined by the test values and is important in determining the hydrophilic character and therefore the solubility of hypromellose. Hypromellose which is sold under the trademark METHOCEL® (The Dow Chemical Company, Michigan, USA) is available in four established strengths that are differentiated from chemistry, as shown in Table 12.

Table 12

For a controlled release matrix tablet formulation, a high rate of hydration / freezing for the rate control polymer, such as hypromellose, can provide the formulation with a protective layer around the center of the tablet. The rates of hydration of the various grades of hypromellose differ due to the difference in chemistry. It has been postulated that a hydroxy propyl group acts as a hydrophilic substitute which greatly contributes to the rate of hydration, while a methoxy group is relatively hydrophobic and does not contribute to the rate of hydration. Hence, the rate of hydration of the different hypromellose chemistries is considered to depend on the ratio of the substitution of hydroxy propoxyl to methoxy, the higher ratio chemists exhibiting faster hydration / gelation. Consequently, E and K chemistry products are more commonly used in controlled release matrix tablets.

The methoxy and hydroxypropoxy content of hypromellose is most commonly measured using a modification of the Zeisel alkoxy reaction, which applies a treatment with hydrogen iodide followed by the gas chromatographic determination of the released isopropyl and methyl iodides (see, for example, The United States Pharmacopoeia (USP30-NF25), United States Pharmacopoeia Convention, Ine., 2007, page 2323 and DOW Analytical Method DOWM 100755-ME00B, The Dow Chemical Company, 2002)). Sample preparation is time-consuming, involves the use of hazardous reagents at elevated temperatures and pressures, and requires careful scrutiny if reliable results are to be achieved.

Proton Nuclear Magnetic Resonance (1H NMR) spectrometry was used to measure the hydroxypropoxy content of 0- (2-hydroxy propyl) cellulose (see, for example, Determination of substituent distribution in cellulose ethers by 13C-and 1H- NMR studies of their acetylated derivatives: 0- (3-hydroxypropyl) cellulose, Tezuka, Y .; Imai, K .; Oshima, M. and Ciba, T., Carbohydr. Res. 196, 1 (1990)). A similar procedure, involving the preparation of an acetyl derivative of the intact polymer to impart solubility in solvent by NMR over a wide substitution interval, has been developed for hypromellose (see, for example, NMR Method 1, below). This procedure demonstrates higher precision than the USP procedure, but sample preparation takes time (3 days are required for the acetylation reaction). The determination of the hydroxypropoxy content of hydroxypropyl cellulose without derivatization, using deuterated chloroform as a solvent, has been described (see, for example, Determination of molar substitution and degree of substitution of hydroxypropyl cellulose by nuclear magnetic resonance spectrometry. , F. F.-L., Kohler, R. R., Ward, G. A., Anal. Chem. 44, 178 (1972)); however, a recent evaluation of this procedure has shown poor reproducibility (see, for example, Determination of the hydroxypropoxy content in hydroxypropyl cellulose by IH NMR. Andersson, T., Richardson, S., Erikson, M., Pharmeuropa 15 , 271 (2003)). Further work was carried out to develop a procedure to determine the content of hydroxy propoxy and the content of methoxy of non-derivatized hypromellose, using the solvent D20 / DMS0, which is suitable for systematic use (see NMR Method 2, under).

NMR Method 1. The degree of substitution is determined indirectly on acetylated samples with proton nuclear magnetic resonance (1H NMR).

Acetylation of the samples is performed by dissolving 75 mg of each of the polymer samples in 2.25 ml of acetic anhydride and 0.75 ml of pyridine. The solutions are heated to 90 ° C under stirring for 6 hours and subsequently dialyzed against deionized water in a Spectra / Por dialysis membrane (with molar mass cut-off at 10 kDa) for 24 hours. The samples are dried before dissolution in deuterated chloroform (0.8 mg / ml). The IH NMR spectra are recorded on a Varian 500 Inova spectrometer (USA) operating at a magnetic field of 11.7 T and equipped with a 5 mm IH gradient inverse detection gradient probe. The free induction decay is recorded with at least 16 scans and the spectral window is between -1 and 16 ppm, with reference to the CDC13 solvent signal. Spectra are recorded at 50 ° C. The weight percentages of the methoxy (MeO) and hydroxy propyl (HP) groups are calculated according to the following formula:

where DS, degree of substitution and MS, molar substitution, were obtained through NMR spectra (see, for example, Determination of the hydroxypropoxy content in hydroxypropyl cellulose by IH NMR. Andersson, T., Richardson, S., Erikson , M., Pharmeuropa 15, 271 (2003)).

NMR method 2. The content of methoxy and hydroxypropoxy is directly determined by Nuclear Magnetic Resonance Spectrometry as follows. 3.5 to about 4.5 mg of hypromellose is dissolved in a solvent, which is 99.96% D20. Hypromellose is heated to approximately 105 ° C for approximately 30 minutes before dissolving in the solvent. Hypromellose is heated to approximately 80 ° C for approximately 15 minutes after dissolving in the solvent. The nuclear magnetic resonance spectrometer includes an inverse IH {X} detection probe. The temperature is about 353K. The pulse is about 45 °. The spectrum width is approximately -2.5 to 13.5 ppm. The pulse repetition is approximately 15 seconds. The broadening of the exponential line is about 1.0 Hz. The spectrum refers to the residual peak of dimethyl sulfoxide (DMSO) at 2.70. The baseline of the nuclear magnetic resonance spectrum is correct. The number of scans is chosen such that the signal: bottom ratio at 200 Hz to the peak at 1.2 ppm is greater than 500. The number of time domain data points is approximately 65,000. The number of data points processed is approximately 250,000.

Table 13 shows the contents of pro-possi hydroxy ("HP") and methoxy ("MeO"), expressed as weight percent of 18 solid dosage forms of a formulation, as determined using the United Staes process. Pharmacopoeia ("USP"), NMR Method 1 and NMR Method 2.

Table 13

Multiple variable analysis identified the hydroxypropoxy hypromellose content to be the most important uncontrolled factor in determining the release of the active ingredient from the formulations. Figure 8 shows the results of the multivariate analysis which identified the hydroxypropyl content of hypromellose of USP 2208 low and high viscosity chemical being the most important uncontrolled factors influencing the release of the active ingredient from the forms. solid dosage of formulations. The vertical axis shows the Variable Influence on Projection, VIP, which is a measure of the relative importance of the factors, listed on the horizontal axis, that can affect the release, (see, for example, PLS. Wold, S., Johansson , E., Cocchi, M. in 3D-QSAR in Drug Design, Theory, Methods and Applications. Kubinyi, H., (Eds), ESCOM Science, Ledien, pages 523-550, 1993).

The factors, in the order shown in Figure 8, are: Polymer ratio (controlled factor used to compensate for the variation in the characteristics of the hypromellose batch), hydroxy propoxy content of hypromellose ("100 cP HP") to low viscosity, high viscosity hypromellose hydroxy propoxy content ("4000 cP HP"), high viscosity hypromellose number average molecular weight ("4000 cP MN"), weight average molecular weight of hypromellose at high viscosity ("4000 cP Mw"), low viscosity hypromellose viscosity ("100 cP Viscosity"), low viscosity hypromellose methoxy content ("100 cP MeO"), high viscosity hypromellose% - through-100-mesh ("4000 cP 100 mesh ,,), average particle diameter of low viscosity hypromellose (" 100 cP PS D50 "), weight average molecular weight of low viscosity hypromellose ( "100 cP Mw"), low viscosity hypromellose% -through-100-mesh ("100 cP 100 mesh ,,), mean diameter of high viscosity hypromellose particles ("4000 cP PS D50"), low viscosity hypromellose number average molecular weight ("100 cP Mn"), high viscosity hypromellose methoxy content (" 4000 cP MeO "), particle size amplitude of low viscosity hypromellose (" 100 cP PS Span "), particle size amplitude of high viscosity hypromellose (" 4000 cP PS Span ") and hypromellose viscosity of high viscosity ("4000 cP Viscosity").

Given the importance of the hydroxypropoxy content, it is important to use the best test procedure. The NMR 2 method, while less robust than the NMR 1 method (especially with regard to transfer between laboratories), has been optimized for the determination of hydroxy propoxy and is considered suitable for routine operation by an experienced operator in a locality. . NMR Method 1 is useful as a reference method or in case operation in multiple locations is a requirement, while the USP Method is suitable for determining compliance with Pharmacopoeia standards but is considered to be too variable to be used in the isolation as a hypromellose batch selection tool. Consequently, unless otherwise specified, the NMR characterization of HPMC refers to NMR Method 2.

Fog point. Aqueous solutions of hypro-mellose undergo a phenomenon known as thermal gelling, whereby, upon heating, gelling will occur at a specific temperature determined by the concentration of the solution and the chemistry of the hypromellose. This effect is attributed to a gradual loss of water of hydration as the temperature rises, which is reflected in a gradual decrease in viscosity. Once dehydration has reached a critical point, the hydrophobic (polymer-polymer) interactions pre-dominate, leading to an expanding lattice structure and a sharp increase in viscosity. The temperature at which the light transmittivity reaches 50% of its original value is called the fog point. The onset of gelation can also be measured (95% transmission temperature) as can a complete temperature - transmission profile.

An illustrative protocol for the determination of the fog point is as follows: Citric acid 50 mL (0.05 M buffer / sodium hydroxide (0.09M) (pH 4.70 - 4.90) in a 100 mL container is heated to 75 ± 5 ° C and 500 ± 2mg of the hypromellose test sample are added with fast stirring. Shaking is continued for approximately 5 minutes to ensure complete dispersion. The container is transferred to an ice bath and slow stirring is continued for an additional 20 minutes The resulting solution is then refrigerated overnight to ensure complete dissolution.

The fog point is measured using a Cloud Point Analyzer such as the Mettler-Toledo FP900 Thermosystem which includes a Mettler-Toledo FP90 central processor and a Mettler fog and transparency measurement cell. -Toledo FP81C. The sample capillaries (Fischer part number UC-18572 or equivalent) are filled with sample solution to a height of about 10 mm by means of a Pasteur pipette, taking care to avoid trapping of air and are placed in the measuring cell. Light transmission is measured continuously while the samples are heated in the temperature range of 40 - 80 ° C at a rate of 1 ° C per minute with a waiting time of 30 s. Each test is carried out in triplicate and the average values for Tcp96 (the temperature at which the light transmission is 96% of the value at 40 ° C) and Tcp50 (the temperature at which the light transmission is 50 % of the value at 40 ° C) are recorded.

Table 14 shows the fog point measurements for 16 solid dosage forms of a formula which has hydroxypropoxy content in the range of 10.2 to 13.7%.

Table 14

Figure 9, based on the data shown in Table 14, shows a weak correlation between the fog point and the hydroxy propoxy content.

Since the haze point is correlated with the hydrophilic character of hypromellose, a property that largely depends on the substitution extent of methoxy and hydroxypropoxy, it is possible that the haze point may be useful as a factor in the reflection. release of the active ingredient, which acts as a substitute for the more complex and expensive NMR methods.

Viscosity. The viscosity of a 2% solution (weight of hypromellose / weight of water) of hypromellose in water can be measured by the Ub belohde viscometer and expressed in centipoise (cp). Further information can be found in C.M. Keary, Characterization of METHOCEL cellulose ethers by aqueous SEC with multiple detectors, Carbohydrate Polymers 45 (2001) 293-303, which is incorporated by reference here in its entirety.

Viscosity and% -through-100-mesh are determined by hypromellose suppliers (for example, Dow Chemical and Shin-Etsu Chemical Companies). Viscosity can be determined using a U.S. hypromellose monograph method. Pharmacopoeia.

Erosion. Solid dosage forms can release the active ingredient by erosion of the hypromellose compact, which can be measured as follows. Hypromellose compacts, which may include Methocel K100 and Metolose SR [Type 90SH] (I-promellose 2208 USP, 100 cP), are prepared by direct compression. Hypromellose is mixed with magnesium stearate (1.5%) in a small V-mixer for 2 minutes. The compacts are prepared using an F press (0.3 x 0.748 "shaped media) at a target weight of 640 mg (+ 10 mg) and a target hardness of 20-25 Kp. Verification of weights and constant hardness values it is carried out by determining the weight and hardness of 5 different compacts before operating the press and once the press has been started randomly selected samples are taken to be sure of consistency.

The erosion studies can be carried out in triplicate by means of a USP I basket apparatus in citric acid buffer 0.05 / NaOH pH 4.8 (900 ml) maintained at 37 ° C and stirred at a speed of 100 rpm. Each compact is weighed before starting the test. The baskets are removed from the medium at 16 hours and dried at 60 ° C in an oven for a period of 24 hours. The residues are subsequently cooled on desiccant before weighing.

The percentage of erosion was calculated as follows:

% erosion = (Wi - W2) * 100 / (Wi),; where Wi is the weight of the compact before the test and W2 is the weight of the cooled residue. Table 15 shows percent erosion for 20 solid dosage forms of a formulation. ; Table 15 ;; ;; Based on the data in Table 15, there is a strong correlation between the release rate of the active ingredient from solid dosage forms that contain low viscosity hypromellose (together with high viscosity hypromellose and other excipients) and erosion of low viscosity hypromellose compacts, as exemplified in Figure 10 for the 12 hour dissolution time point. ; Therefore the erosion test could be used as a performance test in evaluating new batches of low viscosity hypromellose, or to identify and reject those batches that would lead to tablets with unacceptable drug release characteristics or determine a suitable ratio of Low and high viscosity hypromellose which would lead to tablets having acceptable release characteristics. ; Particle size. The particle size can be measured by air jet sieving. Thus, commercially available hypromellose products can be classified in terms of chemistry (hydroxypropoxy and methoxy content), viscosity and physical form (particle size). In the case of METHOCEL <®> products, the classification takes the following form: METHOCEL® X NY P / [P], where X identifies hypromellose as E, F, or K; NY indicates viscosity (N being a number and Y, if present, a letter indicating a multiplier, "C" representing 100 and "M" representing 1000, the multiplicative product being the apparent viscosity in mPa - s, solution to 2 o,; o in H20 at 20 ° C); P is a suffix that, if present, can be used to identify special products ("LV" refers to low viscosity, "CR" to the controlled release degree, "EP" to a product that meets the requirements of the European Pharmacopoeia and so on).; A buffering agent (such as sodium citrate dihydrate) can raise the pH within a core portion of the hydrated tablet, thereby decreasing the solubility of the core to minimize diffusion release For the formulations, the choice of lactose, microcrystalline cellulose and magnesium stearate was carried out in accordance with industrial practice The formulations for the mechanical strength of different tablets are indicated in Table 16.; Table 16 ;; ;; a Pigment mixtures with indicated brightness and color are as follows: SSR 400 mg: 8146W (white); SSR 300 mg: 8580Y (yellow); SSR 200 mg: 7757-Y (yellow); SSR 150 mg: 8146W (white); SSR 50 mg: 7756-OR (orange).; Research has ri veiled a variability of tablet dissolution within a batch of tablets that could not be attributed to any single factor, but depended on four hypromellose factors: viscosity / molecular weight, particle size distribution, count - hydroxy propoxyl content and methoxy content. The relative importance of these factors has been found to vary depending on the strength of the tablet and hypromellose from different suppliers (e.g., Dow Chemical Company and Shin-Etsu, Ltd.) has been found to behave differently. ;; An increase in viscosity (an increase in the length of the chain and therefore in the molecular weight) leads to a reduction in the rate of surface erosion and therefore in the rate of drug release. There is some evidence that this effect can plateau high viscosities. The mixing of high and low viscosity hypromellose to achieve an intermediate viscosity can be modeled using the Phillipof equation: η = (1 KC) <8>, where η = viscosity in cp, K = a constant for each specific batch of the polymer and C = concentration expressed as a percentage. Formulations which include combinations of hypromellose grades may be susceptible to changes in viscosity which may occur as a result of variability within hypromellose batch specifications. ; The effect of intentional change in viscosity determined by adjusting the proportions of high and low viscosity hypromellose 2208, as characterized by weight average molecular weight (Mw), for three batches of tablets, is shown in Figure II. Smaller particles that have a larger surface area to mass ratio hydrate faster than larger particles. This leads to more effective formation of the protective gel barrier. Conversely, tablets made from larger hypromellose particles tend to disintegrate. This leads to the rapid and in-controlled release of the drug. ; Regarding the methoxy and hydroxy propoxyl content, the formulation and preparation procedures are based on theories that are in disagreement with widely accepted assumptions regarding the chemistry of the hypromellose matrix (see, for example, Using Dow Excipients for Controlled Release of Drugs in Hydrophilic Matrix Systems, The Dow Chemical Company, Midland, MI, 2006). It was previously postulated, as mentioned above, that the hydroxypropyl group acts as a hydrophilic substituent which greatly contributes to the rate of hydration, while the methoxy group acts as a relatively hydrophobic substituent and does not contribute to the rate of hydration. The rate of hydration of the different hypromellose chemistries was therefore considered to depend on the ratio of the hydroxypropoxyl: methoxyl substitution. In contrast to this hypothesis, fog point measurements indicated that, for the polymer batches studied, both methoxy and hydroxy propoxy groups act as hydrophobic substituents, such that an increase in the content of one of the two leads to a decrease in the point of fog. The inverse relationship between the hydroxy propyl content and the cloud point for hypromellose batches having a similar level of methoxy substitution is shown in Figure 12. Again, when the hypromellose batches are used in the formulation, all other factors being the same, such a decrease in the mist point leads to an increase in the drug release rate, as shown in Figure 13. quetiapine from the tablets is controlled exclusively by erosion, as illustrated by the coincident release profiles for quetiapine and hypromellose in Figure 14. Thus, changes in methoxyl content and hydroxy propoxyl content affect the rate of erosion. Methods of preparing a formulation include batch-like variation in the ratio of high- and low-viscosity hypromellose to compensate for normal variations in hydroxy propoxyl content, methoxyl content and batch viscosity of hypromellose. which would otherwise lead to unacceptable variability in the dissolution profile of the quetiapine tablets. The processes differ from the conventional "Master Formula" approach, in which each batch of a formulation is prepared identically by delivering the active ingredient and excipients in a fixed amount and by treating them in an identical manner. of the invention, the total content of hypromellose can be fixed for all batches but the ratio of low and high viscosity hypromellose can be different in the different batches, among which the ratio can vary between 15.0: 15.0 and 29.0: 1.0.; The methods of the invention may involve laboratory procedures (e.g., measurement of hydroxy propoxyl by nuclear magnetic resonance) which may reduce the variability with respect to summary test methods. The methods may involve predictive means for determining the ratio of low and high viscosity hypromellose batches to produce a dissolution profile for a given strength formulation. vo can take the form of a look-up table (derived from historical data), a multivariate mathematical model, or any other suitable euristic tool. Processes can improve the frequency with which dosage forms meet drug release specifications for commercial products, support the use of a broad purchase specification for hypromellose batches in compliance with supplier capabilities, allow the use of hypromellose from different suppliers, support the use of different manufacturing locations and scales, and / or support batch manufacturing of dosage forms that have faster or slower release profiles, such as may be required for pharmacokinetic studies. The processes can be applied to the foregoing and other formulations of quetiapine or pharmaceutically acceptable salts thereof, or to formulations which include other active substances and a hypromellose content between 15 and 55%. Some embodiments of the invention include a multivariate model that can be used to correlate hypromellose properties and formulation information to in vitro dissolution measurements of the tablet. The hypromellose content and the hypromellose viscosity have been determined to contribute to the release rate of quetiapine from the quetiapine sustained release tablet formulations. Unexpectedly, not only the hypromellose content and viscosity ratios affect the release rates, but the properties of the polymer [e.g., the hydroxy propoxy content] also affect the release rates. The model may be an artificial neural network model ("ANN"), which may exhibit low prediction errors compared to other models. An ANN is a mathematical procedure for correlating variables with an output. develops a correlation between known inputs and known outputs in a process referred to as "training". A multi-layered Feedforward Neural Network ("NN") has been reported, for example, by Despagne, F. and D. Lue Massart, 1998, "Neural networks in multivariate calibration," Analyst, 123: 157 R-178R, which is incorporated by reference herein in its entirety. A numerical analysis platform sold under the MATLAB trademark, which is available from The MathWorks, Inc. from Natick, Massachusetts, is a commercially available tool for training neural networks and using defined neural networks for prediction. NN feedforward and fast backward propagation are available through a number of commercially available program packages. Figure 15 shows a simplified representation of ANN feedforward with the inputs and outputs related to the formulations of the invention as described herein. Figure 15 shows the input layer 1502, the hidden layer 1504 and the output layer 1506. The properties of hypromellose and the formulation information are inputs to the input layer 1502. The output 1506 is% dissolved, i.e., the% quetiapine released for a single time point. The sustained release dissolution curve of quetiapine tablets as described herein and other pharmaceutically acceptable salts can be modeled using an independent neural network per dissolution sampling time point. The results can be combined to give a dissolution profile that spans different time points. ; An example of ANN architecture for the quetiapine formulations as described herein and other pharmaceutically acceptable salts is reported in Table 17. The articles cited in Table 17 together with the input parameters and the dis- solution, define an ANN used for the quetiapine tablets as described herein (and its pharmaceutically acceptable salts, more particularly the fumarate salt). For the discussion of ANN architecture and the parameters indicated in Table 17, see, for example, Despagne and Massart, 1998 (cited above). Model inputs which may be related to formulations are discussed here and other model inputs may be used for other embodiments of the invention, for example embodiments of the invention which may be used. for other pharmaceutical compositions. Table 17 ;; ;; In some embodiments of the invention, there are two types of training information input into the model 1500. The first type is the formulation information and the second type is the data on specific properties of hypromellose. The strengths of the 50 mg, 200 mg, 300 mg and 400 mg tablets were included in the training of model 1500. The tablets were made according to the protocol shown in Example 2 below. Formulation ingredients and tablet weights were included as inputs (see Ta-bella 18). The quantitative composition of the ingredients was expressed as the relative content (% by weight) of each ingredient for each strength of the tablet. For each batch of any given strength tablet, the only differences in formulation inputs were the amounts of 100 cp hypromellose and 4000 cp hypromellose, although the sum of 100 cp hypromellose and hypromello-sium of 4000 cp it was for each batch 30% by weight of the formulation. All other ingredients in the formulation remained fixed for each formulation strength. ; Table 18; Quetiapine fumarate (% by weight); Lactose monohydrate (% by weight); Microcrystalline cellulose (% by weight); Sodium citrate (% by weight); Hypromellose, 100 cp (% by weight); Hypromellose, 4000 cp (wt%); Magnesium stearate (wt%); Tablet weight (mg); Table 16 shows the quantitative tablet composition of quetiapine formulations as described here and other pharmaceutically acceptable salts of different weights. The second type of training information input into model 1500 was data on the properties of hypromellose. While commercially available data of indicated compliance with the pharmacopoeia standards, such data alone have proved inadequate for understanding the correlation between hypromellose and dissolution results. Eight properties of hypromellose were selected for the model (see Table 19). The values; both for hypromellose at 100 cp and for hypromellose at; 4000 cp for each property were included in the model. ; Table 19; Properties of Hypromellose Abbreviated as Hydroxypropoxy content (% by weight)% HP Methoxy content (% by weight)% MeO Viscosity (cp); Molecular weight:; Weight average MWw; Numeric average MWn Particle size: through 100% <150 pm mesh (150 pm); Mean particle diameter, distribution D50; volume 50% (pm); Amplitude of particle size Amplitude; Methoxy and hydroxypropoxy content can be determined by a spectro-metry protocol Magnetic Resonance Imaging as NMR Method 2.; The values for viscosity and particle size (% -through-100-mesh) can be taken directly from the supplier's certificates of analysis and used in the model. The average particle diameter and particle size amplitude can be determined using a dry powder laser diffraction technique. The number average molecular weight (Mn) and the weight average molecular weight (Mw) are determined using an aqueous SEC process which employs in-line light scattering detection for the direct determination of the molecular weight. The units are Daltons. ; The inputs and outputs in the ANN model training data were mean centered and interval scaled. By means of the change in scale, the maxima of the absolute value of the inputs centered on the average have been set at the value one and the maxima of the absolute values of the outputs centered on the average have been set respectively at the values 0.5, 0.5, 0.5, 0.5 , 0.5, 0.5, 0.8 and 0.85. ; Weights and biases were initialized with small random numbers between -0.05 and 0.05. ; A retro-propagation procedure using momentum and an adaptive learning rate is described below. The algorithm is discussed by Martin T. Hagan, Howard B. Demuth and Mark Beale, Neural Network Design, Boston: PWS Publishing Co., 1996, which is incorporated by reference here in its entirety and is summarized below. ; During the training process, weights and biases are adjusted according to the following formulas (some terms of which are more general than the corresponding terms that appear below in relation to the trained model): ;;; ;; where λ is the learning speed, γ is the moment factor, δ ± is the correction term which is calculated using the standard error back propagation, pj is 1 <1> input to a neuron and t represents the time sequence of the training process. ; The following rules were used to adapt the learning speed to during the training process. The rules involve calculating the squared error, which may be the squared error of a specific prediction, the summation, the squared errors of individual predictions in a training batch, or any other suitable measure of the error between predicted dissolution and real. ; (1) If the quadratic error increases more than 4% after a weight update, the weight update is discarded, the learning speed is multiplied by 0.7 and the moment factor is set to zero; ; (2) If the quadratic error decreases after a weight update, the weight update is accepted and the learning rate is multiplied by 1.05. If the moment factor was previously set to zero, it is reset to its original value; ; (3) If the quadratic error increases by less than 4% after a weight update, the weight update is accepted. The learning speed and the moment factor keep the same values. ; Training was stopped when 400 training epochs or a sum of 0.001 squared goal were reached. The initial learning rate was set at 0.01 and the training lot size was set at 10.; Model 1500 was trained using a training dataset of 177 formulation lots as described here. Tablets of all resistances, two different commercial sources of hypromellose, development and commercial scale producers, and three manufacturing facilities were used to train the model. The tablets included ratios of 100 cp hypromellose to 4000 cp hypromellose ranging from 15:15 to 29: 1 (% -100 cp:% - 4000 cp). Reports are also included in the model. Model 1600 (see Figure 16) is an illustrative predictive trained model based on the model architecture shown in Figure 15 and the training dataset, which inherently reflects the characteristics of the manufacturing equipment that can differ between suppliers and manufacturing plants. Model 1600, therefore, cannot predict the dissolving behavior of the tablets produced by the apparatus which is different from the apparatus used to produce the tablets described herein. Nonetheless, the Model 1600 was trainable to tablets from different manufacturing processes, thus demonstrating that the ANN approach has general applicability, but the models should be trained on the same equipment that is to be used for commercial production. A safeguard against over-fitting is to use the simplest possible ANN to fit the data. Model 1500 is considered an appropriately simple ANN architecture, because it contains a single hidden layer with only 10 cells. ; The training was carried out by obtaining the measurements of the physical properties and chemical properties of the hypromellose batch, entering the measurements in the model, predicting the dissolutions, comparing the expected dissolution to the in vitro dissolution of the tablets into sets made from batches and readjusting model constants until model predictions were acceptable. The protocol for the in vitro dissolution assay is reported in Example 7. The predicted dissolution profile can be compared to a real tablet dissolution profile by calculating the root mean square error of the prediction ( "RMSEP ,,). The lower RMSEP, the better the agreement between the actual and predicted profiles.; For batches of hypromellose at 100 cp and hypromello-sio at 4000 cp, the model 1500 can be used to predict dissolution profiles hypromellose ratios from 15:15 to 29: 1 (100 cp: 4000 cp) in ratio increments of 0.1 (for example, 15.0: 15.0, 15.1: 14.9, 15.2: 14.8, etc.). Figure 17 shows a 1702 range of curves which may include many predicted profiles corresponding to incremental ratios. An optimal profile, and thus an optimal ratio, is identified by comparison of the expected dissolution results at the midpoints in the intervals of the acceptance criterion. dissolution (1704 bars, Figure 17) at 2 points time i, 6 and 12. A comparison of the predicted results and the midpoints is made by calculating a combined relative distance factor, d, using the equation: ;;; ;; where:; P6 is the predicted% quetiapine dissolved at the six hour time point; There is% quetiapine dissolved at the mid-no point in the acceptance criterion range of dissolution at the six hour time point; ; R6 is the acceptance criterion interval in% of quetiapine dissolved at 6 hours; ; Ri2 is acceptance criterion range in% of quetiapine dissolved at 12 hours; ; P12 is the predicted% quetiapine dissolved at the 12 hour time point; ; C12 is the% quetiapine dissolved at the median point in the range of the dissolution acceptance criterion at the 12 hour time point. ; The optimal ratio is identified by selecting the profile with the lowest value of D.; Since the slope of the dissolution profile changes with the particular properties of the hypromelloses used, often the time profiles at the identified optimal ratio may not go through the midpoints of acceptance criterion (as shown by bars 1704 in Figure 17) at 6 or 12 hours. Details of completed batch fabrication using optimal ratio determination are provided above. The twenty-four raw inputs 1610 are scaled to conform to a range of -1 to 1 by the respective scaling factors 1612. The scaled inputs 1614 are fed into the input layer 1602. The scaled inputs 1614 are transformed into the 10 oq values of the hidden layer 1604 (J = 1 to 10) based on the weights 1616 and bias 1618. The values of the hidden layer 1604 are transformed into the output layer value 1606 a of weights 1620 and bia Soutput1622. The value associated next is scaled back to the backscaled output aretroscaiato 1626 using the scale factors 1624.; Table 20 shows illustrative physical parameters of 24 raw 1610 inputs for the 1600 model. The raw inputs numbers 1-16 and 19 - 24 are based on empirical measurements, evaluations or descriptive statistics of the formulation parameters and properties of hypromellose. Raw inputs 17 and 18 are weight percent HPMC for HPMC at 100 and 4000 cp, respectively. Taken together, the raw inputs numbers 17 and 18 represent a ratio which is an independent variable to be optimized based on the distance factor d. The sum of the raw inputs numbers 17 and 18 is kept constant at 30.0% and the ratios between the raw inputs numbers 17 and 18 are varied in steps of 0.1 between 15.0: 15.0 and 29.0: 1.0. ; Table 20 ;; ; ;; Table 20 also shows the maximum and minimum values of each physical raw input parameter for which the model was trained and validated. ; Table 21 shows the corresponding minimum and maximum values of the scaled inputs 1614.; Table 21 ;; ; ;; Model 1600 can be run once for each pair of raw inputs 17 and 18 for each of 8 time points to predict the% dissolution of quetiapine fumarate 1626 (see Figure 16) at time points 6 and 12 hours for different reports. The ratio minimizing the distance factor d can subsequently be used as the ratio for producing the formulas described herein. ; The scaled inputs 1614 can be determined using the following equation. ;; ;; where, for each raw input, p corresponds to a raw input 1610 and a PSCaiato corresponds to a scaled input 1614. xMedium and xScale for each raw input are reported for the example model 1600 in Table 22.; Table 22 ;; ; ;; More generally, in the case where the raw inputs are represented by the vector x, the scalar can be realized as follows: For a given vector x (a column in the input data table), the mean of the vector (xMedia) in the first place is calculated and x is then centered on the mean as below:; <x> mc = * <~> xMean

where I is the identification vector. After a predetermined value of xMax (1 for all raw inputs) it can be used to compute an xScale scale factor using the following equation

The data can then be scaled using the following equation

The output data can be downscaled in a similar way,

The 1626 backscaled output can be determined using the following equation.

where aSCaiatois the value in the output layer 1606, «backscaledis the output backscaled or 1626 and yScala and yMedium are given in Table 23. yScala and yMedium are analogous to xScala and xMedium. yMax is analogous to xMax. yMax is also reported, for the 1600 model, in Table 23.

Table 23

The weights 1616 (an array of 10 x 24 elements), the biases 1618 (a vector 10 x 1), the weights 1620 (a vector 1 x 10) and the biasoutput 1622 (a scalar) for each of the 8 points of time are given in Appen-dice A, below.

The 0iSCaiato output layer 1606 value for each of the time points can be calculated as follows: The illustrative transfer function f is the hyperbolic tangent and is applied to each of the neurons in layers 1604 and 1606. The hyperbolic tangent is defined as :

The value of each of the neurons in the hidden layer 1604 is aj, where J = 1 to 10. The values aj are calculated as follows:

where Wji are the weights 1616, Pscaiatii are the scaled inputs 1614, bj are the biases 1618 and f is defined by f (n]) above.

The value of the neuron in the output layer 1606 (aSCaiato) is given by:

where Wj are the weights 1620, aj are defined above, b2 is with output 1622 and f is defined by f (n) above.

Model 1600 can be executed in MATLAB® by loading the aforementioned variables of the 2-D array, vector and scalar into MATLAB® and performing the calculations defined by the previous equations. It will be understood that the Model 1600 can be run using any suitable numerical analysis platform. The model can be run manually.

Model 1600 can be validated on Leave-One-Out Cross-Validation ("LOOCV") in which a sample of the training dataset is predicted using the remainder of the training dataset. tablet batch was removed from model 1600, which was retrained without the batch. Dissolution of the batch was subsequently predicted using model 1600. The square root of the mean prediction error ("RMSEP") was subsequently calculated by comparing the expected dissolution profile with the real at the specification time points for the profiles in which the real and / or predicted profiles met the dissolution acceptance criteria. This procedure was repeated until all batches of tablets in turn had been left and predicted. The square root of the mean cross-validation error (RMSECV) is the mean of all individual RMSEPs.

RMSECV for Model 1600 for formulations is 2.9% when operating works within the range of the acceptance criteria. The hypromellosis ratio can be determined by targeting the midpoints at the 6 and 12 hour dissolution time points. With acceptance criterion intervals of 22% and 30% at 6 and 12 hours, respectively, an RMSECV of 2.9% for the 1600 model compares favorably with the acceptance criterion ranges.

Model 1600 is an instrument that can be used to increase batch performance as measured by in vitro dissolution of pastes. Consequently, the model is considered verified if the tablets meet the acceptance criteria for dissolution in vitro.

Twenty-four batches of tablets in total, 6 batches of each strength, were produced, at 2 commercial sites, using ratios of 100 cp hypromellose versus 4000 cp hypromellose determined using ANN. Manufacturing details are provided above.

All batches of 200, 300 and 400 mg strength tablets met the dissolution acceptance criteria. Four of the 6 lots of 50 mg strength tablets met the dissolution acceptance criterion. Two batches of the 50 mg paste failed to meet the acceptance criterion and these batches were made from the same 100 cp and 4000 cp hypromellose batches at each of the two commercial production sites. Since the model was trained based on the commercial availability of hypromellose, there are hypromellose compositions that are under-represented in training. For example, the 4,000 cp hydroxypropoxy (10%) hypromellose content of non-positive batches is a content level that is not well represented in training tablets.

The development of the Model 1600 has shown that refinement of the model, for example, based on the increase in the number of hypromellose batches and tablet batches, the variety of formulation strengths and possibly other variables, can increase. the robustness of the model.

The data corresponding to the tablets on which the Model 1600 has been trained are shown below in Table 24.

Table 24

HPMC Dissolution (%)

Resistance pa 100cp 4000cp 1 hour 2 hours 4 hours 6 hours 8 hours 12 hours 16 hours 20 hours sticca (%) (%)

50 24 6 13.2 23.3 43.5 56.5 62.5 75.9 90.6 100.7 50 24 6 12.9 22.8 43.4 56.8 63.4 76.9 90.6 99.9 50 24 6 13.9 24.1 44.3 57.3 63.7 77.1 90.2 99.7 50 24 6 13.5 23.8 45.6 59.8 67.5 85.6 101.6 107.2 50 24 6 13.7 25.1 48.1 63.3 72.2 95.2 105.4 106.2 50 24 6 13.4 24.0 45.9 60.8 68.7 88.7 102.6 104.9 50 24 6 19.5 32.1 57.2 73.5 87.0 103.0 104.1 103.9 50 24 6 20.2 31.2 53.4 68.4 77.9 100.3 106.1 107.1 50 24 6 16.3 26.8 48.1 61.9 68.5 85.8 98.5 102.3 50 24 6 13.2 24.4 46.1 60.5 67.7 85.0 100.6 105.9 50 22 8 12.8 23.1 42.8 56.7 62.9 76.2 90.0 100.8 50 23 7 15.4 25.3 44.0 57.0 62.8 72.0 82.8 93.1 50 23 7 12.9 23.4 43.8 57.9 64.5 79.2 93.8 102.8 50 23 7 13.5 23.9 44.0 57.9 64.6 79.8 95.1 104.6 50 23 7 13.5 24.0 45.2 59.4 66.4 83.3 97.9 102.7 50 23 7 13.9 24.9 44.8 59.8 65.8 81.0 95.5 103.3 50 23 7 13.1 23.7 42.9 56.5 62.4 75.9 89.6 99.9 50 23 7 15.0 24.6 43.3 56.8 62.9 74.6 87.4 99.1 50 23 7 13.0 23.1 42.8 57.1 63.6 78.2 93.7 102.8 50 23 7 12.2 21.4 39.5 53.2 59.0 71.5 86.3 99.0 50 23 7 13.9 23.4 41.8 55.0 60.5 71.2 83.7 96.1 50 23 7 12.9 22.4 40.2 53.4 58.9 70.0 83.2 96.1 50 23 7 13.1 22.9 40.7 54.2 59.7 70.9 83.5 95.6 50 23 7 13.2 23.1 42.2 56.2 62.2 75.1 89.3 101.0 50 23 7 13.5 23.4 42.6 57.0 63.4 77.2 91.9 103.3 50 23 7 15.4 25.7 44.8 58.2 63.9 75.3 88.6 100.5 50 23 7 12.8 23.0 42.0 55.6 61.4 73.4 87.2 99.1 50 23 7 12.5 22.4 40.9 54.2 59.8 72.2 85.7 97.1 50 23 7 13.1 23.1 41.8 55.1 61.1 73.1 87.0 98.5 50 23 7 13.5 23.4 41.6 54.6 60.0 70.6 82.8 95.1 50 23 7 14.0 24.0 42.6 55.8 61.6 75.0 89.6 100.6 50 23 7 13.0 22.8 41.2 54.2 59.4 70.0 82.0 93.7 50 23 7 12.9 22.7 41.1 54.4 60.0 71.1 84.8 96.8 50 23 7 12.5 21.2 38.3 51.3 56.8 69.2 83.1 95.8 50 23 7 12.7 21.6 38.9 52.2 57.8 68.3 82.5 95.5 50 23 7 13.7 23.9 43.3 57.2 63.2 76.1 91.0 101.7 HPMC Dissolution (%)

Resistance pa- lOOcp 4000cp 1 hour 2 hours 4 hours 6 hours 8 hours 12 hours 16 hours 20 hours sticca (%) (%)

200 23 7 10.6 21.1 42.6 59.0 68.1 82.2 92.6 97.8 200 23 7 10.1 20.3 41.3 57.3 66.1 79.7 90.6 96.6 200 23 7 9.5 19.4 39.7 55.2 63.2 75.5 88.2 98.0 200 23 7 10.8 21.6 44.6 63.2 76.5 97.4 101.3 101.4 200 23 7 13.3 23.4 45.1 62.0 71.7 89.5 101.6 104.6 200 23 7 10.2 18.8 36.3 49.5 56.2 66.0 76.7 87.4 200 23 7 9.6 19.6 39.5 54.4 61.8 72.8 83.7 92.4 200 23 7 9.8 19.7 39.7 55.1 63.1 75.6 87.9 96.0 200 23 7 9.5 19.5 39.4 54.9 63.2 77.0 89.8 95.9 200 23 7 9.6 19.7 39.9 55.2 63.7 77.3 89.8 97.9 200 23 7 8.9 18.1 36.6 50.5 58.0 69.1 80.8 91.0 200 23 7 8.4 16.4 31.9 43.4 49.4 58.2 65.4 73.2 200 23 7 10.0 20.8 42.7 60.0 69.6 85.1 95.7 100.2 200 23 7 10.0 20.1 40.9 56.5 64.5 76.9 87.5 93.5 200 23 7 9.7 20.2 41.5 57.0 64.7 76.8 87.9 94.6 200 23 7 10.4 21.2 43.1 59.4 67.7 82.1 94.0 99.5 200 23 7 10.0 20.4 41.3 57.0 64.8 77.4 89.7 96.6 200 23 7 10.1 20.6 42.0 57.6 65.7 78.6 89.9 95.2 200 23 7 9.5 19.2 39.4 54.9 62.9 76.1 88.3 95.6 200 23 7 10.5 21.0 42.8 58.8 67.0 80.5 92.2 98.7 200 23 7 11 22 43 60 68 83 95 98 200 23 7 12 23 44 61 72 93 99 100 200 23 7 9 18 35 48 55 63 71 80 200 23 7 9.8 19.8 39.7 54.2 61.9 73.7 87.0 96.5 200 23 7 9.6 19.0 38.1 52.5 59.9 71.4 84.7 95.6 200 23 7 9.0 18.6 38.5 53.5 61.3 73.7 85.8 95.0 200 23 7 10.4 20.3 40.2 55.0 62.2 73.7 87.0 96.5 200 23 7 9.1 18.1 36.0 49.6 56.3 65.9 79.7 93.5 200 23 7 10.0 20.6 41.5 57.1 65.6 79.5 91.4 97.9 200 23 7 9.7 19.7 39.8 55.5 63.8 77.3 89.4 97.0 200 23 7 9.7 19.7 40.0 55.9 64.3 77.8 90.3 98.0 200 23 7 11.0 21.2 41.8 58.0 66.8 81.0 91.8 97.3 200 23 7 10.0 21.3 44.3 62.0 74.3 93.5 98.8 101.1 200 23 7 10.5 21.6 44.7 62.5 73.8 92.1 98.8 101.5 200 23 7 9.3 19.1 38.6 53.7 61.1 72.6 86.2 96.3 300 25 5 9.4 19.8 41.0 56.8 65.4 80.6 91.7 95.4 300 25 5 11.3 22.8 46.1 64.5 78.5 97.7 101.1 101.7 300 25 5 11.5 22.6 44.4 61.6 74.2 93.7 99.8 102.0 HPMC Dissolution (%)

Resistance pa- lOOcp 4000cp 1 hour 2 hours 4 hours 6 hours 8 hours 12 hours 16 hours 20 hours sticca (%) (%)

300 25 5 10.5 19.7 37.4 50.4 56.9 65.7 74.8 83.9 300 25 5 9.4 20.1 41.8 58.0 66.2 78.5 88.2 92.8 300 25 5 9.0 19.0 39.4 55.0 63.6 77.7 89.3 94.5 300 25 5 9.0 18.8 38.4 52.9 60.4 71.8 83.4 91.7 300 25 5 8.7 18.4 37.9 53.1 61.3 74.8 88.3 95.5 300 25 5 8.3 18.0 37.7 53.1 60.9 75.6 90.6 95.5 300 25 5 9.1 18.8 38.2 52.8 59.4 70.6 83.9 92.4 300 25 5 9.4 18.9 37.7 51.7 58.0 66.9 77.9 88.5 300 25 5 9.8 20.7 42.2 58.8 67.9 82.9 94.6 99.9 300 25 5 9.0 19.0 38.6 53.4 61.0 72.9 84.8 92.4 300 25 5 9.6 19.9 40.5 58.5 67.3 81.0 91.1 95.8 300 25 5 8.9 18.8 38.4 53.3 60.4 71.6 84.1 91.1 400 27 3 9.5 20.2 41.4 57.0 66.6 82.1 91.7 95.2 400 27 3 10.4 22.4 46.0 63.2 73.2 87.6 93.4 95.8 400 27 3 10.3 22.3 45.8 62.7 72.7 87.0 93.3 95.8 400 27 3 11.1 23.4 48.1 65.8 79.7 97.5 101.0 101.7 400 27 3 11.2 23.0 46.6 64.1 77.5 94.9 98.0 99.2 400 27 3 10.3 20.2 39.5 53.9 61.4 74.0 85.9 94.5 400 27 3 11.2 23.6 48.5 66.6 81.1 97.7 100.1 100.8 400 27 3 11.7 24.2 49.2 67.2 81.0 97.5 100.1 100.7 400 22 8 8.7 17.3 34.6 47. 4 55.1 66.3 76.1 84.7 400 27 3 9.3 20.2 41.5 57.3 67.0 82.4 92.2 95.2 400 27 3 9.2 20.0 41.1 56.2 64.3 77.0 88.1 94.2 400 27 3 9.8 21.6 44.6 61.0 70.9 86.5 94.5 96.5 400 27 3 9.8 21.2 43.9 60.4 71.5 88.2 95.7 97.5 400 27 3 9.1 19.9 40.9 56.1 64.5 77.9 90.0 96.1 400 27 3 9.5 21.0 43.7 60.1 70.6 87.1 94.0 95.9 400 27 3 9.6 21.0 43.3 59.4 68.8 87.3 96.5 98.4 400 27 3 9.3 19.7 40.4 55.3 62.9 76.3 89.5 94.9 400 27 3 9.4 20.6 42.2 57.9 65.8 79.7 90.6 94.5 400 27 3 9.5 20.1 41.0 56.6 65.6 81.8 91.7 94.3 400 27 3 10.0 22.1 46.6 63.5 76.6 91.0 94.3 96.0 400 27 3 10.0 21.7 44.5 60.9 70.1 85.6 94.1 96.3 50 29 1 20.0 33.0 57.0 73.0 92.0 102.0 102.0 103.0 50 29 1 18.0 29.0 47.0 58.0 62.0 72.0 87.0 99.0 50 29 1 24.0 38.0 63.0 82.0 lOO.o 102.0 102.0 103.0 50 29 1 17.0 27.0 45.0 57.0 61.0 70.0 80.0 94.0 50 29 1 21.0 34.0 57.0 72.0 85.0 104.0 105.0 105.0 HPMC Dissolution (%)

Resistance pa- lOOcp 4000cp 1 hour 2 hours 4 hours 6 hours 8 hours 12 hours 16 hours 20 hours sticca (%) (%)

200 29 1 13.0 26.0 52.0 71.0 84.0 101.0 102.0 102.0 200 29 1 12.0 25.0 49.0 66.0 74.0 92.0 99.0 102.0 200 29 1 12.0 20.0 36.0 48.0 53.0 60.0 69.0 84.0 200 29 1 13.0 26.0 53.0 72.0 85.0 102.0 103.0 103.0 200 29 1 13.0 24.0 49.0 64.0 70.0 85.0 95.0 98.0 300 29 1 12.0 24.0 48.0 66.0 78.0 98.0 101.0 101.0 300 29 1 12.0 23.0 46.0 63.0 72.0 91.0 97.0 99.0 300 29 1 8.0 17.0 35.0 47.0 53.0 61.0 77.0 88.0 300 29 1 12.0 24.0 48.0 67.0 79.0 99.0 101.0 102.0 300 29 1 12.0 22.0 42.0 56.0 62.0 81.0 99.0 100.0 400 29 1 12.0 24.0 49.0 66.0 79.0 94.0 97.0 99.0 400 29 1 12.0 25.0 50.0 67.0 77.0 90.0 95.0 97.0 400 29 1 10.0 20.0 39.0 52.0 58.0 66.0 77.0 87.0 400 29 1 12.0 25.0 50.0 68.0 79.0 93.0 96.0 97.0 400 29 1 11.0 22.0 44.0 59.0 67.0 85.0 97.0 99.0 50 22 8 18.0 30.0 54.0 71.0 86.0 103.0 103.0 103.0 50 22 8 22.0 32.0 53.0 67.0 75.0 93.0 103.0 103.0 50 22 8 16.0 25.0 44.0 57.0 62.0 74.0 87.0 98.0 50 22 8 18.0 26.0 42.0 53.0 56.0 61.0 67.0 72.0 50 22 8 16.0 25.0 41.0 51.0 56.0 63.0 70.0 76.0 50 22 8 1 6.0 26.0 43.0 55.0 60.0 71.0 82.0 95.0 50 22 8 16.0 21.0 42.0 54.0 59.0 65.0 73.0 81.0 200 22 8 11.0 21.0 43.0 60.0 73.0 94.0 102.0 103.0 200 22 8 10.0 19.0 38.0 53.0 62.0 76.0 92.0 101.0 200 22 8 9.0 18.0 35.0 49.0 56.0 66.0 76.0 85.0 200 22 8 9.0 16.0 28.0 37.0 41.0 47.0 53.0 58.0 200 22 8 10.0 17.0 30.0 40.0 44.0 50.0 56.0 60.0 200 22 8 9.0 16.0 30.0 41.0 46.0 54.0 60.0 68.0 300 22 8 9.0 19.0 39.0 50.0 67.0 88.0 100.0 102.0 300 22 8 9.0 17.0 34.0 48.0 56.0 69.0 86.0 97.0 300 22 8 9.0 17.0 34.0 47.0 53.0 62.0 69.0 75.0 300 22 8 8.0 13.0 24.0 31.0 35.0 40.0 45.0 49.0 300 22 8 8.0 15.0 28.0 39.0 44.0 52.0 58.0 64.0 400 22 8 9.0 19.0 38.0 54.0 67.0 86.0 97.0 99.0 400 22 8 8.0 17.0 34.0 48.0 58.0 75.0 91.0 96.0 400 22 8 9.0 18.0 37.0 51.0 59.0 73.0 88.0 92.0 400 22 8 8.0 15.0 28.0 38.0 43.0 50.0 56.0 64.0 400 22 8 8.0 15.0 29.0 40.0 46.0 54.0 61.0 68.0 HPMC Dissolution (%)

Resistancepa- lOOcp 4000cp 1 hour 2 hours 4 hours 6 hours 8 hours 12 hours 16 hours 20 hours sticca (%) (%)

400 22 8 9.0 16.0 32.0 43.0 50.0 58.0 67.0 80.0 50 15 15 16.0 26.0 46.0 60.0 68.0 88.0 99.0 100.0 50 15 15 18.0 27.0 43.0 57.0 60.0 69.0 78.0 87.0 50 15 15 19.0 27.0 43.0 55.0 60.0 68.0 75.0 82.0 50 15 15 16.0 23.0 35.0 43.0 48.0 53.0 58.0 62.0 50 15 15 16.0 23.0 36.0 44.0 49.0 54.0 58.0 62.0 50 15 15 14.0 21.4 34.0 42.8 47.0 53.0 57.6 61.0 200 15 15 9.0 17.0 34.0 48.0 59.0 76.0 93.0 103.0 200 15 15 8.0 14.0 27.0 36.0 41.0 49.0 55.0 61.0 200 15 15 8.0 15.0 28.0 38.0 44.0 53.0 60.0 65.0 200 15 15 8.0 13.0 22.0 28.0 32.0 37.0 41.0 45.0 200 15 15 8.0 12.0 21.0 28.0 31.0 36.0 40.0 44.0 200 15 15 7.0 12.0 22.0 29.0 32.0 37.0 42.0 46.0 300 15 15 8.0 15.0 29.0 42.0 52.0 68.0 84.0 97.0 300 15 15 7.0 13.0 25.0 35.0 41.0 50.0 58.0 65.0 300 15 15 7.0 13.0 24.0 32.0 37.0 44.0 50.0 55.0 300 15 15 7.0 11.0 19.0 25.0 28.0 32.0 36.0 39.0 300 15 15 7.0 12.0 20.0 26.0 28.0 33.0 36.0 39.0 300 15 15 6.0 10.0 17.0 22.0 25.0 29.0 33.0 36.0 400 15 15 7.0 14.0 30.0 42.0 53.0 70.0 83.0 92.0 400 15 15 7.0 13.0 25.0 35.0 42.0 51.0 60.0 69.0 400 15 15 7.0 13.0 26.0 37.0 43.0 53.0 60.0 67.0 400 15 15 7.0 11.0 19.0 25.0 28.0 32.0 36.0 40.0 400 15 15 6.0 11.0 20.0 26.0 30.0 35.0 40.0 43.0 400 15 15 6.0 11.0 22.0 30.0 34.0 41.0 46.0 51.0 50 15 15 20.3 29.0 44.6 55.9 60.5 68.2 76.4 85.2 50 15 15 17.6 25.7 39.8 50.2 54.5 60.7 65.8 70.0

Table 25 lists the characteristics of the

100 cp hypromellose batches used for training

the model 1600.

Table 25

HP MeO CoA_100 CoA Viscosity Mw Mn Particles D50 Particles (% weight) (% weight) mesh Width 10.4 27.4 96.5 103 131000 46800 82.1 2.21 10.8 27.6 91.2 96 131000 43900 64.0 2.00 10.5 28.2 93.0 102 124000 47000 104.1 2.42 HP MeO CoA_100 CoA Viscosity Mw Mn Particles D50 Particles (% weight) (% weight) mesh Width 10.5 29.0 91.8 105 131300 41300 77..7 2.55 10.6 29.0 92.9 96 123000 43800 83..4 2.29 10.7 28.7 94.8 97 133300 38500 66..3 2.66 10.8 27.7 95.0 112 136000 45600 83..2 2.63 10.6 29.2 91.2 102 133000 44600 78..6 2.67 11.8 26.4 93.7 103 138000 44800 72..3 2.69 13.4 29.1 94.9 103 147000 51 400 77..7 2.75 9.8 28.5 94.6 101 130000 42 800 69 .. 7 2.39 10.6 28.4 93.0 110 130000 43100 68..4 2.59 10.7 27.9 92.8 100 128000 39500 71..1 2.96 9.9 28.9 96.2 108 136000 56500 63..3 2.87 9.9 28.8 92.8 112 142000 42100 63..1 2.46 11.2 27.9 95.8 100 125000 43000 68..9 2.76 10.6 27.5 96.6 103 134000 46500 75..7 2.56 10.6 28.2 100.0 102 130000 55000 67..4 2.09 10.7 28.5 100.0 101 130000 55000 65..7 2.14 10. 7 28.5 100.0 104 131000 56000 64..3 2.10

Table 26 lists the characteristics of the lots.

ti of hypromellose at 4000 cp used to train the

model 1600.

Table 26

HP MeO CoA_100 CoA Viscosity Mw Mn Particles D50 Particles (% weight) (% weight) mesh Width 11.3 28.8 95.0 5280 351000 130200 75.4 2.55 11.3 27.8 93.8 3684 327000 112000 67.9 2.57 11.6 29.0 90.0 5436 328000 101300 81.1 2.46 12.1 27.3 91.7 4184 304000 84000 75.0 2.93 11.9 28.5 95.0 5151 350300 94400 80.5 2.25 11.6 28.1 92.0 4782 331000 110000 107.6 2.25 11.5 29.0 93.2 4556 333000 140000 88.2 2.44 10.6 27.7 93.8 4829 331000 97000 81.5 2.57 10.8 28.7 91.6 5227 332000 94700 92.3 2.52 9.9 28.2 95000 991 3962 2.53 10.0 28.6 93.5 5535 325000 105000 55.3 2.83 12.8 27.6 90.7 4591 325000 118000 88.8 2.60 11.4 29.0 96.6 5005 329000 101000 80.9 2.07

Figure 18 shows an illustrative method 1800 for formulating a sustained release formulation. The method may include step 1810 of measuring dihydroxy propoxy and methoxy of a plurality of hypromellose batches using nuclear magnetic resonance (NMR). Among this plurality, a first batch can have a first viscosity and a second batch can have a second viscosity. Step 1820 shows input into a multivariable model of the hydroxy propoxy content and molecular weight of the first and second batches and a tablet strength. Step 1830 shows the entry into the model of a series of ratios between a quantity of the first lot and a quantity of the second lot. Step 1840 shows the identification, using the model, of an optimal ratio that corresponds to an expected dissolution profile that has a deviation from an objective profile, the deviation being smaller than that of the other reports. Figure 19 shows the illustrative procedure 1900. Method 1900 may include the step 1910 of identifying a plurality of formulation parameter values. The method 1900 may include the step 1920 of identifying a plurality of property parameter values. Phase 1930 shows the selection of the plurality of ratio values. Each ratio value can correspond to a ratio of the first constituent to the second constituent. Step 1940 shows the identification of a ratio value which minimizes a difference between an expected dissolution fraction of a target constituent and a predetermined acceptable dissolution fraction of the target constituent.

Figure 20 shows the illustrative look-up table 2000 which can be used to correlate the ratio 2140 of wt% release control excipient 2120 and 2130 to the release information 2150 of the active ingredient. The 2150 information may include 2152 percent released of the active ingredient at time 2154. The 2150 information may be determined in whole or in part by one or more physical or chemical parameters 2122 and 2132 of the 2120 release control excipients. and 2130, respectively. Parameters 2122 and 2132 can be stored in ranges such as ranges 2124 and 2134, respectively. The information 2150 can be determined in whole or in part by the strength 2110 of the dosage form. The look-up table 2000 can be populated by empirically determining the information 2150 for all combinations of resistance values 2110, parameters such as 2122, parameters such as 2132 and ratio 2140. In some embodiments of the Invention, the look-up table 2000 can be populated partially by empirically determining the information 2150 for the values and partially by evaluating the values. For example, some values of information 2150 may be interpolated or extrapolated based on neighboring values.

In some embodiments of the invention, the release control excipients 2120 and 2130 may be hypromelloses having nominal viscosities of 100 cp and 4000 cp, respectively. In some embodiments of the invention, the active ingredient may be quetiapine. In some embodiments of the invention, parameters such as 2122 and 2132 may correspond to inputs at model 1600 (shown in Figure 16; see, for example, inputs 1-16 in Table 17).

Exemplification

• Example 1: Determination of the hydroxy propyl (HP) content of hypromellose (hypromellose) by nuclear magnetic resonance.

According to NMR Method 2, 3.5 to about 4.5 mg of hypromellose is dissolved in a solvent, which is 99.96% D20. The hypromellose is heated to approximately 105 ° C for approximately 30 minutes before dissolving in the solvent. The hypromellose is heated to approximately 80 ° C for approximately 15 minutes after dissolution in the solvent. The nuclear magnetic resonance spectrometer includes an inverse detection probe of <1> H {X}. The temperature is about 353K. The pulse is about 45 °. The spectrum width is approximately -2.5 to 13.5 ppm. The pulse repetition is approximately 15 seconds. The widening of the exponential line is about 1.0 Hz. The spectrum is referred to the residual peak of dimethyl sulfoxide (DMSO) at 2.70 ppm. The base line of the nuclear magnetic resonance spectrum is correct. The number of scans is chosen such that the signal: bottom ratio at 200 Hz for the peak at 1.2 ppm is greater than 500. The number of time domain data points is approximately 65,000. The number of data points processed is about 250,000.

The NMR spectrum is made so that the peaks at 4.5 ppm and 1.2 ppm are symmetrical.

The following regions are integrated: Region 1: 4.96 - 4.31, which is Area A; Region 2: 4.08 - 2.95, which is Area B; and Region 3: 1.47 - 0.92, which is Area C.

The content of hydroxy propoxy (% by weight HP) is calculated as:

% by weight HP = {(75) / [di x MoleHP 162 (58 x MoleHP) (14 x MoleMeO)]} x 100, wherein: MoleHP c (3 x A); MoleMeO = [B-C- (6 x A)] / (3 x A); and MeO is methoxy.

The following is an exemplary procedure for analysis of the hydroxy propyl (HP) content of hypromellose by NMR.

According to NMR Method 2, a sample of 3.5 to 4.5 mg of hypromellose is heated to about 105 ° C for about 30 minutes. The sample from 3.5 to 4.5 mg of hypro-mellose is dissolved in 99.96% of D20. The dissolved hypromellose is heated to about 80 ° C for about 10 minutes. Dissolved hypromellose is analyzed by nuclear magnetic resonance whereby (i) the nuclear magnetic resonance spectrometer includes an inverse detection probe at <1> H {X}, (ii) the temperature is about 353K, ( iii) the pulse is about 45 °, (iv) the spectrum width is about -3.5 to 13.5 ppm, (v) the pulse repetition is about 15 seconds, (vi) the broadening of the line exponential is approximately 1.0 Hz, (vii) the number of scans is selected such that the signal: bottom ratio at 200 Hz for the peak at 1.2 ppm is greater than 500, (viii) the number of data points of time domain is about 65,000 and (ix) the number of data points processed is about 25,000.

The nuclear magnetic resonance spectrum is made so that the peaks at 4.5 ppm and 1.2 ppm are not symmetrical. The spectrum refers to the residual peak of DMSO at 2.70 ppm. The baseline of the nuclear magnetic resonance spectrum is correct.

The following regions are integrated: Region 1: 4.96 - 4.31, which is Area A; Region 2: 4.31 - 4.08; Region 3: 4.08 - 2.95, which is Area B; Region 4: 2.95 -2.45; and Region 5: 1.47 - 0.92, which is Area C.

The content of hydroxy propoxy (% by weight of HP) is calculated as: Weight% HP = {(75) x MoleHP 162 (58 x MoleHP) (14 x MoleMeO)]} x 100, where (i) MoleHP = C / (3 x A) and (ii) MoleMeO = [B-C- (6 x A)] / (3 x A).

Example 2: Formulation of the 50 mg tablet The following process was used to produce the prolonged release formulations of quetiapine fumarate shown in Table 1.

1) Mixing of quetiapine fumarate, lactose, microcrystalline cellulose, hypromellose 2208 (USP) and sodium citrate (for example, in a high shear granulator) until content uniformity is achieved (for example, 600 L Fielder for about 10 minutes);

2) loading purified water (for example, 37% of the weight of the tablet) on the powder in the granulator (for example, spray nozzle) for 5-6 minutes to form a granulate;

3) Drying of the granulate in a fluidized bed dryer (for example, to a water content <or equal to 3% loss on drying);

4) Reduction of the granulate particle to provide a suitable flow by compression (e.g., Carr index not exceeding 30 (e.g., 20) using e.g. a 0.05 to 0.109 inch mill screen; and

5) Mixing of the granulate with the magnesium stearate for some time sufficient to prevent the formation of a noticeable film on the tablet punch (for example, 3 minutes in a V-mixer; for 2/3 full).

The resulting formulation of step 5 is compressed to form a tablet with a hardness greater than 16 kilopond) (kgf) (especially about 28 kp) and a friability less than 1%.

The tablets can be further coated by mixing all coating ingredients in water until dissolved and spraying the resulting mixture onto the tablets (e.g. in a perforated tray coating device) until a uniform coating is achieved (e.g. , a target of 2.5% percent by weight).

Example 3: Formulation of the 150 mg tablet The procedure described in Example 2 was followed to produce the tablets of the composition indicated in Table 2.

Example 4: Formulation of the 200 mg tablet The procedure described in Example 2 was followed to produce the tablets of the composition indicated in Table 3.

Example 5: Formulation of the 300 mg tablet The procedure described in Example 2 was followed to produce the tablets of the composition indicated in Table 4.

Example 6: Formulation of the 400 mg tablet The procedure described in Example 2 was followed to produce the tablets of the composition indicated in Table 5.

Example 7: In vitro dissolution assay - 50 mg In vitro dissolution protocol

The following procedure was used for ANN training, formulation control, and as a predictor of in vivo release. The dissolution process is carried out by means of the well known basket apparatus at a rotation speed of 200 rpm. Initially, 900 ml of dissolution medium consisting of 0.05 M (molar) sodium citrate and 0.09 N (normal) sodium hydroxide are placed in each vessel. The pH of this medium is 4.8. At 5 hours, 100 ml of a medium consisting of 0.05 M sodium phosphate and 0.46 N sodium hydroxide are added to each vessel to bring the pH of the medium to 6.6 for the final duration of the dissolution analysis. Samples are taken over a 20 hour time period and analyzed for quetiapine using ultraviolet spectrophoto-metric detection at 290 nm.

Figure 21 shows the results of the dissolution assay. The error bars correspond to spans of single measurements at each time point.

Example 8: In vitro dissolution assay - 150 mg The in vitro dissolution protocol carried out as in Example (7). Figure 22 shows the results of the dissolution assay. The error bars correspond to the interval of the individual measurements at each time point.

Example 9: In vitro dissolution assay - 200 mg The in vitro dissolution protocol carried out as in Example (7). Figure 23 shows the results of the dissolution assay. The error bars correspond to the interval of the individual measurements at each time point.

Example 10: In vitro dissolution assay - 300 mg The in vitro dissolution protocol carried out as in Example (7). Figure 24 shows the results of the dissolution assay. The error bars correspond to the interval of the individual measurements at each time point.

Example 11: In vitro dissolution assay - 400 mg The in vitro dissolution protocol carried out as in Example (7). Figure 25 shows the results of the dissolution assay. The error bars correspond to the interval of the individual measurements at each time point.

Example 12: Blood Plasma Protocol Studies A multi-center, open-label, multiple-dose study was performed to evaluate steady-state pharmaco-kinetics of commercial-grade tablets including study formulations ("SF" ) which have the following quetiapine strengths: 50 mg, 200 mg, 300 mg and 400 mg. The study formulations have compositions that are listed in Tables 1-5. After a two-day wash-out period (elimination) , patients received oral doses of the study formulations and immediate release medication ("IR") that is now available under the brand name "Seroquel" (now available from AstraZeneca Pharmaceuticals, Wilmington, Delaware) once daily as follows: 50 mg SF on Days 1 - 4, 200 mg SF on Days 5 - 7, 300 mg SF on Days 8 - 11, 400 mg SF on Days 12 - 14 and 300 mg IR on Days 15 - 17. On Days 4 and on, the patients ate a breakfast with a high percentage of g standardized ratios of their predicted dose in 10 minutes. Data from Day 3 (mg 50; Figure 3), Day 7 (mg 200; Figure 4), Day 10 (mg 300; Figure 5), and Day 14 (mg 400; Figure 6) were used and it was assumed that steady state had been achieved for each dose level. In each curve (Figures 3-6), the bars correspond to a prediction interval (p = 0.05) for the individual subject data. Each curve (Figures 3-6) also shows a best fit curve calculated using the first order constants Kadi drug absorption and elimination rate Ka, respectively, with the equation

The best-fit parameters for the resistances of the different pads are as follows:

mg 50: Base = 0.3773; Ke = 0.8421; Ka = 0.05765 (3)

200 mg: Base = 25.86; Ke = 0.3541; Ka = 0.1033 (4)

mg 300: Base = 42.15; Ke = 0.2592; Ka = 0.1033 (5)

400 mg: Base = 62.96; Ke = 0.2959; Ka = 0.1390 (6)

Figure 7 shows the data from Figures 3-6.

Thus, the prolonged release formulations comprising quetiapine and its pharmaceutically acceptable salts and the processes for making the formulations have been provided. Those skilled in the art will appreciate that the invention can be carried out in embodiments other than those described herein, presented for illustrative rather than limiting purposes and that the invention is limited only by the appended claims.

APPENDIX

TABLE Al— 5

Time point: 1

Layer: 1604 (See FIG. 16)

Neuron Weight

i = l i = 2 i = 3 i = 4 i = 5 i = 6

Neuron Weight

i = 7 i = 8 i = 9 i = 10 i = 11 i = 12

TABLE Al— 5 (cont.)

Neuron Weight

i = 13 i = 14 i = 15 i = 16 i = 17 i = 18

Neuron Weight

i = 19 i = 20 i = 21 i = 22 i = 23 i = 24

TABLE Al-6

Time point: 1

Layer: 1206 (ve-

TABLE A2-5

Time point: 2

Layer: 1604 (See FIG. 16)

Neuron Weight

i = l i = 2 i = 3 i = 4 i = 5 i = 6

Neuron Weight

i = 7 i = 8 i = 9 i = 10 i = 11 i = 12

TABLE A2-5 (cont.)

Neuron Weight

i = 13 i = 14 i = 15 i = 16 i = 17 i = 18

Neuron Weight

i = 19 i = 20 i = 21 i = 22 i = 23 i = 24

TABLE A2-6

Time point: 2

Layer: 1606 (see FIG. 16)

TABLE A3-5

Point of

time: 3

Layer: 1604 (See FIG. 16)

Neuron Weight

i = l i = 2 i = 3 i = 4 i = 5 i = 6

Neuron Weight

i = 7 i = 8 i = 9 i = 10 i = 11 i = 12

TABLE A3-5 (cont.)

Neuron Weight

i = 13 i = 14 i = 15 i = 16 i = 17 i = 18

Neuron Weight

i = 19 i = 20 i = 21 i = 22 i = 23 i = 24

TABLE A3-6

Time point: 3

Layer: 1606 (see FIG. 16)

TABLE A4— 5

Time point: 4

Layer: 1604 (See FIG. 16)

Neuron Weight

i = l i = 2 i = 3 i = 4 i = 5 i = 6

Neuron Weight

i = 7 i = 8 i = 9 i = 10 i = 11 i = 12

Neuron Weight

i = 13 i = 14 i = 15 i = 16 i = 17 i = 18

TABLE A4 - 5 (cont.)

Neuron Weight

i = 19 i = 20 i = 21 i = 22 i = 23 i = 24

TABLE A4 -6

Time point: 4

Layer: 1606 (see FIG. 16)

TABLE A5-5

Time point: 5

Layer: 1604 (See FIG. 16)

Neuron Weight

i = l i = 2 i = 3 i = 4 i = 5 i = 6

Neuron Weight

i = 7 i = 8 i = 9 i = 10 i = 11 i = 12

TABLE A5-5 (cont.)

Neuron Weight

i = 13 i = 14 i = 15 i = 16 i = 17 i = 18

Neuron Weight

i = 19 i = 20 i = 21 i = 22 i = 23 i = 24

Table A5-6

Time point: 5

Layer: 1606 (see FIG. 16)

TABLE A6-5

Time point: 6

Layer: 1604 (See FIG. 16) Neuron Weight

TABLE A6-5 (cont.)

Neuron Weight

i = 13 i = 14 i = 15 i = 16 i = 17 i = 18

Neuron Weight

i = 19 i = 20 i = 21 i = 22 i = 23 i = 24

Table A6-6

Time point: 6

Layer: 1606 (see Fig. 16)

TABLE A7-5

Time point: 7

Layer: 1604 (See FIG. 16)

Neuron Weight

i = l i = 2 i = 3 i = 4 i = 5 i = 6

Neuron Weight

i = 7 i = 8 i = 9 i = 10 i = 11 i = 12

TABLE A7-5 (cont.)

Neuron Weight

i = 13 i = 14 i = 15 i = 16 i = 17 i = 18

Neuron Weight

i = 19 i = 20 i = 21 i = 22 i = 23 i = 24

TABLE A7-6

Time point: 7

Layer: 1606 (see FIG. 16)

TABLE A8-5

Time point: 8

Layer: 1604 (See FIG. 16)

Neuron Weight

i = l i = 2 i = 3 i = 4 i = 5 i = 6

Neuron Weight

i = 7 i = 8 i = 9 i = 10 i = 11 i = 12

TABLE A8-5 (cont.)

Neuron Weight

i = 13 i = 14 i = 15 i = 16 i = 17 i = 18

Neuron Weight

i = 19 i = 20 i = 21 i = 22 i = 23 i = 24

TABLE A8-6

Time point: 8

Layer: 1606 (see FIG. 16)

Claims (26)

CLAIMS 1. Formulation comprising quetiapine or a pharmaceutically acceptable salt thereof in which the quetiapine content is from about 9.6% to about 10.4% by weight and in which the formulation comprises about 30% hydroxy propyl methyl cellulose by weight and about 7%. 2% sodium citrate dihydrate by weight. 2. The formulation of claim 1 wherein the quetiapine content is from about 49.5 to about 50.5 mg. 3. Formulation of claim 2 comprising 30.0% hydroxy propyl methyl cellulose by weight. 4. Wording of claim 3 wherein: about 15 to about 29 of 30% of the hydroxy propyl methyl cellulose by weight is a first constituent of hydroxy propyl methyl cellulose; the remaining 30.0% is a second constituent of hydroxy propyl methyl cellulose; And the first and second constituents correspond, respectively, to a first gradation of hydroxy propyl methyl cellulose which has an apparent viscosity between about 80 cp and about 120 cp and a second hydroxy propyl methyl cellulose which has an apparent viscosity between about 3000 of the criminal code and about 5600 of the criminal code. 5. Wording of claim 4 which further comprises: about 25.1% of lactose monohydrate by weight; about 25.1% microcrystalline cellulose by weight; And about 1% magnesium stearate by weight. 6. Formulation comprising quetiapine or a pharmaceutically acceptable salt thereof in which the quetiapine content is from about 25.6 to about 26.5% by weight and wherein the dosage form comprises about 30% hydroxy propyl methyl cellulose by weight. and about 12.5% sodium citrate dihydrate by weight. 7. Formulation of claim 6 wherein the quetiapine content is from about 149.5 to about 150.5 mg. 8. Formulation of claim 7 comprising 30.0% hydroxy propyl methyl cellulose by weight. 9. Wording of claim 8 in which: about 15 to about 29 of 30% of the hydroxy propyl methyl cellulose is a first constituent of hydroxy propyl methyl cellulose; the remaining 30.0% is a second constituent of hydroxy propyl methyl cellulose; And the first and second constituents correspond, respectively, to a first gradation of hydroxy propyl methyl cellulose which has an apparent viscosity between about 80 cp and about 120 cp and a second hydroxy propyl methyl cellulose which has an apparent viscosity between about 3000 of the criminal code and about 5600 of the criminal code. 10. Wording of claim 8 further comprising: about 13.0% lactose monohydrate by weight; about 13.0% microcrystalline cellulose by weight; And about 1.5% magnesium stearate by weight. 11. Formulation comprising quetiapine or a pharmaceutically acceptable salt thereof in which the quetiapine content is from about 32.9 to about 33.8% by weight and wherein the dosage form comprises about 12.5% sodium citrate dihydrate by weight. and about 30% hydroxy propyl methyl cellulose by weight. 12. Formulation of claim 11 wherein the quetiapine content is from about 199.5 to about 200.5 mg. 13. Formulation of claim 12 comprising 30.0% hydroxy propyl methyl cellulose by weight. 14. The formulation of claim 13 wherein: about 15 to about 29 of 30% of the hydroxy propyl methyl cellulose by weight is a first constituent of hydroxy propyl methyl cellulose; the remaining 30.0% is a second constituent of hydroxy propyl methyl cellulose; And the first and second constituents correspond, respectively, to a first gradation of hydroxy propyl methyl cellulose which has an apparent viscosity between about 80 cp and about 120 cp and a second hydroxy propyl methyl cellulose which has an apparent viscosity between about 3000 of the criminal code and about 5600 of the criminal code. 15. Wording of claim 11 further comprising: about 8.8% of lactose monohydrate by weight; about 8.8% microcrystalline cellulose by weight; And about 1.5% magnesium stearate by weight. 16. Formulation comprising quetiapine or a pharmaceutically acceptable salt thereof in which the quetiapine content is from about 37.1% to about 38.0% by weight and wherein the dosage form comprises from about 12.5% sodium citrate dihydrate by weight. and about 30% hydroxy propyl methyl cellulose by weight and wherein about 15 to about 29 of 30% hydroxy propyl methyl cellulose is a first constituent of hydroxy propyl methyl cellulose; the remaining 30% is a second constituent of hydroxy propyl methyl cellulose; and the first and second constituents correspond, respectively, to a first grade of hydroxy propyl methyl cellulose which has an apparent viscosity between about 80 cp and about 120 cp and a second hydroxypropyl methyl cellulose which has an apparent viscosity between about 3000 cp and about 5600 cp, in which the ratio of the first gradation of hydroxypropyl methyl cellulose to the second gradation of hydroxypropyl methyl cellulose is not from 25.0 to 5.0 17. Formulation comprising quetiapine or a pharmaceutically acceptable salt thereof in which the quetiapine content is from about 45.5% to about 46.4% by weight and wherein the dosage form comprises about 11.5% of sodium citrate dihydrate in weight and about 30% of hydroxy propyl methyl cellulose by weight. 18. Formulation of claim 17 wherein the quetiapine content is from about 399.5 to about 400.5 mg. 19. The formulation of claim 18 comprising 30% hydroxy propyl methylcellulose by weight. 20. The formulation of claim 19 wherein: about 15 to about 29 of 30.0% hydroxy propyl methyl cellulose is a first constituent of hydroxy propyl methyl cellulose; the remaining 30.0% is a second constituent of hydroxy propyl methyl cellulose; And the first and second constituents correspond, respectively, to a first gradation of hydroxy propyl methyl cellulose which has an apparent viscosity between about 80 cp and about 120 cp and a second hydroxypropyl methyl cellulose which has an apparent viscosity between about 3000 of the criminal code and about 5600 of the criminal code. 21. Wording of claim 17 further comprising: about 1.8% lactose monohydrate by weight; about 1.8% microcrystalline cellulose by weight; And about 2.0% magnesium stearate by weight. 22. Formulation of any one of claims 1, 6, 11, 16, 17 which satisfies the following dissolution criteria, when dissolution occurs in a basket apparatus which has a rotational speed of 200 rpm and which contains 900 milliliters of 0.05 molar sodium citrate and 0.09 normal sodium hydroxide, to which 100 milliliters of 0.05 molar sodium phosphate and 0.46 normal sodium hydroxide are added after 5 hours: no more than 20% of the quetiapine is dissolved during the first one hour period of dissolution; 47-69% of the quetiapine is dissolved during the first six hour period of dissolution; 65-95% of the quetiapine is dissolved during the first 12 hour period of dissolution; at least 85% of the quetiapine is dissolved during the first 20 hour period of dissolution. 23. A method for effectively treating psychosis in humans, comprising oral administration to a human patient on a once daily basis of an oral extended-release dosage form containing quetiapine. or a pharmaceutically acceptable salt thereof in which the quetiapine content is 50 mg which in the steady state provides a time to the maximum concentration in plasma (tmax) of the antipsychotic said in from about 2 to about 16 hours, a maximum concentration plasma (Cmax) which is greater than or equal to four times the plasma concentration of the said antipsychotic at approximately 24 hours and which dosage form provides effective treatment of psychosis for approximately 24 hours or more after administration to the patient . 24. A method for effectively treating psychosis in humans, including the oral administration to a human patient on a once daily basis of an oral extended-release dosage form containing quetiapine. or a pharmaceutically acceptable salt thereof in which the quetiapine content is 150 mg which in the steady state provides a time to the maximum concentration in plasma (tmax) of the antipsychotic said in from about 2 to about 16 hours, a maximum concentration plasma (Cmax) which is greater than or equal to four times the plasma concentration of the said antipsychotic at approximately 24 hours and which dosage form provides effective treatment of psychosis for approximately 24 hours or more after administration to the patient . 25. A method for effectively treating psychosis in humans, comprising oral administration to a human patient on a once daily basis of an oral extended-release dosage form containing quetiapine. or a pharmaceutically acceptable salt thereof in which the quetiapine content is 200 mg which in the steady state provides a time to the maximum concentration in plasma (tmax) of the antipsychotic said in from about 2 to about 8 hours, a maximum concentration plasma (Cmax) which is greater than or equal to four times the plasma concentration of the said antipsychotic at approximately 24 hours and which dosage form provides effective treatment of psychosis for approximately 24 hours or more after administration to the patient . 26. A method for effectively treating psychosis in humans, comprising oral administration to a human patient on a once daily basis of an oral extended-release dosage form containing quetiapine. or a pharmaceutically acceptable salt thereof in which the quetiapine content is 400 mg which in the steady state provides a time to the maximum concentration in plasma (tmax) of the antipsychotic said in from about 3 to about 8 hours, a maximum concentration plasma (Cmax) which is greater than or equal to four times the plasma concentration of the said antipsychotic at approximately 24 hours and an area under the curve between the time of administration and 24 hours after administration (AUCcum, 24) which is greater than -re or equal to about 6000 ng.hour / ml and which dosage form provides effective treatment of psychosis for about 24 hours or more after administration to the patient.