HK1157317B - Crystalline polymorphic forms of monosodium n-[8-(2-hydroxybenzoyl)amino]caprylate - Google Patents

Description

Crystalline polymorph of monosodium N- [8- (2-hydroxybenzoyl) amino ] caprylate

The application is a divisional application of Chinese patent application No. 200580013993.5, which has an application date of 2005-5-6, a priority date of 2004-5-6 and 2004-10-15.

The benefit of U.S. provisional application Ser. No. 60/569,476, filed on 6/5/2004 and U.S. provisional application Ser. No. US60/619,418, filed on 15/10/2004, both of which are incorporated herein by reference.

Technical Field

The present invention relates to crystalline polymorphic forms of monosodium N- [8- (2-hydroxybenzoyl) amino ] caprylate, amorphous monosodium N- [8- (2-hydroxybenzoyl) amino ] caprylate, pharmaceutical compositions containing them, processes for their preparation, and methods of using them to facilitate the delivery of active agents.

Background

U.S. Pat. No. 5,650,386 discloses N- [8- (2-hydroxybenzoyl) amino ] octanoic acid and its salts and its use in facilitating the delivery of various active agents.

Disclosure of Invention

Summary of The Invention

The present invention relates to polymorphic forms of monosodium N- [8- (2-hydroxybenzoyl) amino ] caprylate ("SNAC"), including two hydrates of SNAC, a methanol/water co-solvate, and an ethanol/water co-solvate. More specifically, the present invention provides six polymorphic forms of SNAC (hereinafter referred to as forms I-VI). The invention also provides amorphous forms of SNAC.

One embodiment of the present invention is a pharmaceutical composition comprising: (A) (ii) one or more of forms I-VI of SNAC and/or (ii) amorphous SNAC; and (B) an active agent, such as heparin. According to a preferred embodiment, the pharmaceutical composition comprises at least about 20, 30, 40, 50, 60, 70, 80, 90, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight of one of forms I-VI of SNAC or amorphous SNAC, based on 100% total weight of SNAC in the pharmaceutical composition. According to another preferred embodiment, the pharmaceutical composition comprises at least about 20, 30, 40, 50, 60, 70, 80, 90, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight of one of forms I-VI of SNAC based on 100% total weight of crystalline SNAC in the pharmaceutical composition.

Another embodiment of the invention is a method of administering an active agent or facilitating its delivery to an animal, such as a human, by administering a pharmaceutical composition of the invention.

Another embodiment is a method of treating thrombosis in an animal, such as a human, in need of such treatment by orally administering an anti-thrombotic effective amount of a pharmaceutical composition of the invention comprising heparin.

Another embodiment is a method of making form I of SNAC comprising the steps of: form III, V or VI of SNAC, or a mixture thereof, is heated to at least 50 ℃ (but preferably below 110 ℃) for a time sufficient to form I of SNAC.

Another embodiment is a method of making form I of SNAC comprising the steps of: the amorphous SNAC is heated at about 30 to about 90 ℃, and preferably about 40 to about 80 ℃ for a time sufficient to form I of SNAC.

Another embodiment is a method of making form I of SNAC comprising the step of lyophilizing any form of SNAC other than form I to form I. For example, the method can include lyophilizing one or more of forms II-VI of SNAC and/or amorphous SNAC to form I.

Another embodiment is a pharmaceutical composition, such as a tablet, comprising a milled (e.g., ball milled) or directly compressed mixture of form I of SNAC with at least one active agent and/or pharmaceutically acceptable additive (such as described below). The pharmaceutical composition may be prepared by milling (e.g., ball milling) or compressing (e.g., direct compression) a mixture of form I of SNAC and at least one active agent and/or pharmaceutically acceptable additive.

Another embodiment is a method of making form II of SNAC comprising the steps of: drying (e.g., drum drying) a solvate of SNAC (e.g., an ethanol solvate or a methanol solvate) without agitation and contacting the dried SNAC with moisture for a time sufficient to form II of SNAC. Preferably, the drying and contacting steps are performed in a closed vessel. The dried SNAC was stored in a humid environment to convert any remaining amorphous form II SNAC to form II.

Another embodiment is a pharmaceutical composition, such as a tablet, comprising a directly compressed mixture of form II of SNAC and at least one active agent and/or pharmaceutically acceptable additive (such as described below). The pharmaceutical composition may be prepared by compressing a mixture of form II of SNAC with at least one active agent and/or pharmaceutically acceptable additive (such as described below).

Another embodiment is a method of making form III of SNAC comprising the steps of: exposing form I, II, IV, V, or VI of SNAC, or a mixture thereof, to an environment having a relative humidity of 75%, 80%, 85%, 90%, or more than 90% for a time sufficient to form III.

Another embodiment is a method of making form III of SNAC comprising the steps of: the amorphous form is exposed to moisture (i.e., an environment having a relative humidity greater than 0% and preferably greater than 5 or 10% I) for a time sufficient to form III.

Another embodiment is a method of making form III of SNAC comprising the steps of: form I, II, IV, V or VI of SNAC or amorphous SNAC or mixtures thereof (with or without one or more active agents and/or pharmaceutically acceptable additives such as those described below) are wet granulated for a time sufficient to form III.

Another embodiment is a method of making form III of SNAC comprising the steps of: exposing form V or VI of SNAC, or a mixture thereof, to an environment having a relative humidity of 30%, 35%, 40%, 50%, or more than 50% for a time sufficient to form III.

Another embodiment is a method of making form III of SNAC comprising the steps of: exposing form VI of SNAC to an environment having a relative humidity of 10%, 20%, 30%, or more than 30% for a time sufficient to form III.

Another embodiment is a method of making form III of SNAC comprising the step of crystallizing SNAC from water.

Another embodiment is a method of making form III of SNAC comprising the step of wet granulating form I of SNAC for a time sufficient to form III.

Another embodiment is a pharmaceutical composition, such as a tablet, comprising a mixture of directly compressed form III of SNAC and an active agent and/or pharmaceutically acceptable additives (such as those described below). The pharmaceutical composition may be prepared by direct compression of a mixture of form III of SNAC and an active agent and/or pharmaceutically acceptable additive.

Another embodiment is a method of making form IV of SNAC comprising the steps of: form I, II, IV, V, or VI of SNAC, or a mixture thereof, is heated to a temperature of about 110 or 150 ℃ to the melting point of SNAC (e.g., at 150 or 170 ℃) for a time sufficient to form IV.

Another embodiment is a method of making form V of SNAC comprising the step of crystallizing SNAC from a methanol solution at a relative humidity of at least 30, 40, or 50%. Preferably, the methanol is substantially or completely free of water. Without being bound to any particular theory, it is believed that the methanol solvate may exchange methanol for water in the air over a period of time, thereby producing methanol-water solvate form V. For example, form V can be prepared by preparing a saturated solution of SNAC (e.g., form I-IV or VI of SNAC, or a mixture thereof) in methanol at a relative humidity of at least 30, 40, or 50% and cooling the solution, e.g., to room temperature or below (such as in an ice bath). The resulting precipitate may be filtered and dried.

Another embodiment is a method of making form V of SNAC comprising the step of equilibrating forms I-IV or VI of SNAC using methanol. Preferably, the methanol solution is substantially or completely free of water. For example, form V can be prepared by slurrying any one of forms I-IV or VI or a mixture thereof in methanol at a relative humidity of at least 30, 40, or 50% and maintaining the slurried mixture at ambient temperature for a time sufficient to form V (e.g., for several days).

Another embodiment is a method of making form VI of SNAC comprising the step of crystallizing SNAC from an ethanol solution at a relative humidity of at least 30, 40, or 50%. Preferably, the ethanol solution is substantially or completely free of water. For example, form VI can be prepared by preparing a saturated solution of SNAC (e.g., form I-V of SNAC, or a mixture thereof) in ethanol at a relative humidity of at least 30, 40, or 50% and cooling the solution to, for example, room temperature or below.

Another embodiment is a method of making form VI of SNAC comprising the step of slurrying any of forms I-V in ethanol at a relative humidity of at least 10, 20, or 30%. Preferably, the ethanol solution is substantially or completely free of water. For example, form VI can be prepared by adding any one of forms I-V to ethanol to form a precipitate and maintaining the slurry mixture at ambient temperature for a time sufficient to form VI.

Another embodiment is a method of preparing amorphous SNAC by dehydrating form III of SNAC (e.g., in vacuo) for a time sufficient to form amorphous SNAC.

Drawings

Fig. 1,6, 11, 16, 21, 26 and 43 are X-ray powder diffraction patterns (XRPD) of crystalline forms I-VI and amorphous SNAC (containing about 10% of SNAC form III) of SNAC prepared as in examples 1-6 and 14, respectively.

Figures 2, 7, 12, 17, 22, 27 and 44 are Differential Scanning Calorimetry (DSC) analyses of crystalline forms I-VI and amorphous SNAC (containing about 10% SNAC form III) of SNAC as prepared in examples 1-6 and 14, respectively.

Figures 3, 8, 13, 18, 23, 28, and 45 are thermogravimetric analyses (TGA) of crystalline forms I-VI and amorphous SNAC (containing about 10% SNAC form III) of SNAC prepared as in examples 1-6 and 14, respectively.

Fig. 4,9, 14, 19, 24, 29, and 46 are FTIR spectra of crystalline forms I-VI and amorphous SNAC (containing about 10% SNAC form III) of SNAC prepared as in examples 1-6 and 14, respectively.

Fig. 5, 10, 15, 20, 25, 30, and 47 are humidity absorption/desorption spectra of crystalline forms I-VI and amorphous SNAC (containing about 10% SNAC form III) of SNAC prepared as in examples 1-6 and 14, respectively.

Figures 31 and 32 are graphical representations of plasma heparin concentration in cynomolgus monkeys versus time after oral administration of capsules of form I or III of SNAC and heparin as prepared in example 7.

Figure 33 is a graphical representation of plasma heparin concentration versus time in cynomolgus monkeys after oral administration of capsules of form I or III of SNAC and heparin as prepared in example 7.

Figures 34 and 35 are graphical representations of plasma heparin concentration in cynomolgus monkeys versus time after oral administration of capsules of form I or III of SNAC and heparin as prepared in example 8.

Figure 36 is a graphical representation of plasma heparin concentration versus time in cynomolgus monkeys after oral administration of capsules of form I or III of SNAC and heparin as prepared in example 8.

Figure 37 is a graphical representation of the amount by weight of precipitate of form I or III of SNAC dissolved in deionized water at 37 ℃ and 15 minutes (example 9).

Fig. 38 is a graphical representation of the amount by weight of precipitate of form I, II, III, or IV of SNAC dissolved in deionized water at 37 ℃ and over 15 minutes (example 9).

Figure 39 shows an XRPD of form I of SNAC before and after ball milling (example 11).

Figure 40 shows the XRPD of form I of SNAC before and after wet granulation (example 12).

Figure 41 shows an XRPD of form I of SNAC before and after compression (example 13).

Figure 42 shows an XRPD of form III of SNAC before and after compression (example 13).

Detailed Description

Detailed Description

Definition of

The term "polymorph" refers to a crystallographically distinct crystalline form of a substance.

The term "hydrate" as used herein includes (but is not limited to): (i) a material containing molecularly bound water and (ii) a crystalline material containing one or more crystalline water molecules or a crystalline material containing free water.

The term "SNAC" as used herein refers to monosodium N- [8- (2-hydroxybenzoyl) amino ] caprylate. The term "SNAC" as used herein, unless otherwise indicated, refers to all polymorphs of SNAC.

The term "SNAC 1/3 hydrate" as used herein refers to a crystalline form of SNAC crystals in which one molecule of water is bound to three molecules of SNAC.

The term "SNAC trihydrate" as used herein refers to a crystalline form of SNAC crystals in which three molecules of water are associated with each molecule of SNAC.

The term "solvate" as used herein includes, but is not limited to, a molecular or ionic complex of a molecule or ion of a solvent with a molecule or ion of SNAC. The term "co-solvate" as used herein includes, but is not limited to, a molecular or ionic complex of a molecule or ion of two or more solvents with a molecule or ion of SNAC.

The term "delivery agent" as used herein refers to SNAC, including polymorphic forms of its crystals.

An "effective amount of a drug" is an amount of an active agent (e.g., heparin) effective to treat or prevent a condition in a living organism to which the drug is administered for a period of time, e.g., an amount of active agent that produces a therapeutic effect at a desired dosing interval. Those skilled in the art recognize that effective dosages will depend upon the route of administration, the use of excipients, and the possibility of co-use with other active agents for the treatment of disease.

The term "treating" as used herein refers to administering an active agent for the purpose of curing, alleviating, altering, treating, ameliorating, improving or affecting a condition (e.g., a disease), a symptom of a disease, or a predisposition toward a disease.

An "effective amount of a delivery agent" is an amount of the delivery agent that facilitates absorption of a desired amount of the active agent by any route of administration, such as those discussed herein, including, but not limited to, the oral (e.g., through a biofilm in the gastrointestinal tract), nasal, pulmonary, dermal, vaginal, and/or ocular routes.

The term "heparin" as used herein refers to all crystalline forms of heparin, including, but not limited to, unfractionated heparin, heparin analogs, dermatans, chondroitins, low molecular weight heparins (e.g., tinzaparin (including tinzaparin sodium)), very low molecular weight heparins, and ultra-low molecular weight heparins. Preferably the type of heparin is unfractionated heparin, such as sodium heparin (e.g. sodium heparin USP). The term "low molecular weight heparin" as used herein generally refers to at least 80% (by weight) heparin has a molecular weight of about 3000 to about 9000 daltons of heparin. Non-limiting examples of low molecular weight heparins include tinzaparin, enoxaparin (enoxaprin), and dalteparin (daltiparin). Tinzaparin has been approved by the FDA for administration in combination with warfarin sodium for the treatment of acute deep vein thrombosis with or without pulmonary embolism. The sodium salt of tinzaparin may be sold under the trademark Innohep^TMAvailable from pharmon Corporation of boulder, co. The term "very low molecular weight heparin" as used herein generally refers to heparin in which at least 80% (by weight) of the heparin has a molecular weight of about 1500 to about 5000 daltons. Non-limiting examples of very low molecular weight heparins include bemiparin. The term "ultra-low molecular weight heparin" as used herein generally refers to heparin in which at least 80% (by weight) of the heparin has a molecular weight of about 1000 to about 2000 daltons. Non-limiting examples of ultra-low molecular weight heparin include fondaparinux (fondaparinux).

The term "insulin" as used herein refers to all crystalline forms of insulin, including, but not limited to, naturally occurring insulin and synthetic insulin, such as those described in U.S. patents US 4,421,685, US 5,474,978, and US 5,534,488, each of which is incorporated herein by reference in its entirety.

The term "AUC" as used herein refers to the area under the plasma concentration-time curve as calculated by the trapezoidal rule over the complete dosing interval, e.g. a 24 hour interval.

The term "mean" as used herein, unless otherwise indicated, represents the arithmetic mean of the pharmacokinetic values prior to the pharmacokinetic value (e.g., mean peak).

The term "about" as used herein means within 10% of a given value, preferably within 5% of a given value, and more preferably within 1% of a given value. Alternatively, the term "about" as used herein means that values of this type may fall within scientifically acceptable tolerances, depending on how qualitatively the measurements are given as available tools.

Anhydrous SNAC crystal form I

Crystalline polymorph form I of SNAC is anhydrous. Form I is stable at room temperature and does not change form when subjected to milling (e.g., ball milling) or compression (e.g., direct compression). However, form I does transform to form III when wet granulation is performed with sufficient water for a sufficient time. Form I has a melting point onset at about 198 ℃ according to Differential Scanning Calorimetry (DSC) (see figure 2). Form I of SNAC has an XRPD pattern substantially the same as shown in figure 1. Characteristic XRPD peak locations (expressed in degrees 2 θ ± 0.2, 0.1, 0.05, or 0.01 ° 2 θ) and d-spacings for form I are provided in table 1 below. The XRPD peak locations marked "(U)" in table 1 are unique to form I. For example, peaks at 2.98 ° 2 Θ ± 0.2, 0.1, 0.05, or 0.01 ° 2 Θ are unique to form I.

Table 1: characteristic XRPD peaks (expressed in degrees 2 theta) of form I of SNAC

Form I can be prepared by the method described in example 1 below.

Form I can also be prepared by heating form III, V or VI or a mixture thereof to a temperature of at least 50 ℃ (but preferably not more than 110 ℃).

Form I can also be prepared by heating amorphous SNAC at about 30 to about 90 ℃, and preferably at about 40 to about 80 ℃ for a time sufficient to form I of SNAC.

Another method of preparing form I produces form I by lyophilizing any form of SNAC other than form I. For example, one or more of forms II-VI of SNAC and/or amorphous SNAC can be lyophilized to provide form I.

The invention also provides a pharmaceutical composition comprising form I of SNAC wherein less than 90, 80, 70 or 60% of the SNAC is crystalline (based on 100% total weight of SNAC).

The present invention also provides pharmaceutical compositions, such as tablets, comprising a milled (e.g., ball milled) or directly compressed mixture of form I of SNAC and at least one active agent and/or pharmaceutically acceptable additive, such as those described below. Preferably, the pharmaceutical composition (or milled or directly compressed mixture) comprises at least 50, 60, 70, 80, 90, 95, 96, 97, 98 or 99% of form I, based on the total weight of SNAC in the pharmaceutical composition (or milled or directly compressed mixture).

Crystalline form II of SNAC hydrate

Crystalline polymorph form II is a hydrate of SNAC. Without being bound to any particular theory, the present inventors have established the following: form II is 1/3 hydrate (i.e., it carries about 1 mole of water per 3 moles of SNAC (also known as SNAC 1/3 hydrate)). Form II is stable at room temperature. Form II has a melting point onset of about 199 ℃ according to DSC (see figure 7). Form II of SNAC has an XRPD pattern substantially the same as shown in figure 6. Characteristic XRPD peak locations (expressed in degrees 2 θ ± 0.2, 0.1, 0.05, or 0.01 ° 2 θ) and d-spacings for form II are provided in table 2 below. The XRPD peak locations marked "(U)" in table 2 are unique to form II. For example, peaks at 3.29, 11.96, and 17.76 ° 2 Θ ± 0.2, 0.1, 0.05, or 0.01 ° 2 Θ are unique to form II.

TABLE 2 characteristic XRPD peaks (expressed in degrees 2 θ) for form II of SNAC

Form II of SNAC can be prepared by drying (e.g., drum drying) a solvate of SNAC (e.g., an ethanol solvate or a methanol solvate) without agitation and contacting the dried SNAC with moisture for a time sufficient to form II of SNAC. Preferably, the drying and contacting steps are performed in a closed vessel. The contacting step may be performed after the drying step. The dried SNAC can optionally be stored in a humid environment (e.g., ambient conditions or a humidified environment (e.g., relative humidity of 10 or 20% or above 20%)) to convert any remaining SNAC that is not SNAC form II to form II. The ethanol solvate of SNAC can be prepared by the method described in example 2.

SNAC hydrate form III

Crystalline polymorph form III is a hydrate of SNAC. Without being bound to any particular theory, the present inventors have established the following: form III is a trihydrate (i.e., it carries about 3 moles of water per mole of SNAC (also known as SNAC trihydrate)). Form III is stable at room temperature and does not change form when compressed (e.g., direct compression). Form III has a melting point onset of about 198 ℃ according to Differential Scanning Calorimetry (DSC) (see fig. 12). Form III of SNAC has an XRPD pattern substantially the same as shown in figure 11. Characteristic XRPD peak locations (expressed in degrees 2 θ ± 0.2, 0.1, 0.05, or 0.01 ° 2 θ) and d-spacings for form III are provided in table 3 below. The XRPD peak locations marked "(U)" in table 3 are unique to form III. For example, peaks at 6.69, 13.58, and 16.80 ° 2 Θ ± 0.2, 0.1, 0.05, or 0.01 ° 2 Θ are unique to form III.

TABLE 3 characteristic XRPD peaks (expressed in degrees 2 θ) for form III of SNAC

Form III can be prepared by the following steps: contacting form I, II, IV, V or VI, or a mixture thereof, with an environment having a relative humidity of 75%, 85%, 90%, or more than 90% for a time sufficient to form III (e.g., 7 days or more than 7 days). For example, form III can be prepared by contacting any of forms I, II or IV-VI for at least 7 days with an environment having a relative humidity of 75% or above 75% (e.g., until the water content in the material is at least about 15% w/w). If the moisture content in the material is significantly greater than 15% w/w, it is preferred to dry the material under ambient conditions until the material has a moisture content of about 15% w/w.

Form III may be prepared by exposing amorphous SNAC to moisture (i.e., an environment having a relative humidity greater than 0% and preferably greater than 5 or 10%) for a time sufficient to form III.

Form III can also be prepared by wet granulation (aqueous granulation) of form I, II, IV, V or IV of SNAC or amorphous SNAC or mixtures thereof. One embodiment is wet granulation of form I. The resulting form III can then be used again (e.g., at 50 ℃) to obtain form I of SNAC.

Another method of preparing form III is by contacting form V or VI of SNAC, or a mixture thereof, with an environment having a relative humidity of 30%, 35%, 40%, 50%, or 50% or more for a time sufficient to form III. Another method of preparing form III is performed by contacting form VI of SNAC, or a mixture thereof, with an environment having a relative humidity of 10%, 20%, 30%, or 30% or more for a time sufficient to form III.

Form III can also be prepared by crystallizing SNAC from water. The crystals formed are isolated, for example, by filtration and drying at ambient conditions. Drying is preferably carried out at temperatures below 40 or 35 ℃.

The present invention also provides pharmaceutical compositions, such as tablets, comprising a mixture of directly compressed form III of SNAC with at least one active agent and/or pharmaceutically acceptable additive (such as those described below). Preferably, the pharmaceutical composition (or direct compressed mixture) comprises at least 50, 60, 70, 80, 90, 95, 96, 97, 98 or 99% by weight of form III based on the total weight of SNAC in the pharmaceutical composition (direct compressed mixture).

Anhydrous SNAC crystal form IV

Crystalline polymorph form IV of SNAC is anhydrous. Form IV is stable at room temperature. In addition, form IV is less soluble in acetonitrile and is thermodynamically more stable than form I at ambient conditions. Form IV has a melting point onset of about 199 ℃ according to Differential Scanning Calorimetry (DSC) (see fig. 17). Form IV of SNAC has an XRPD pattern substantially the same as shown in figure 16. Characteristic XRPD peak locations (expressed in degrees 2 θ ± 0.2, 0.1, 0.05, or 0.01 ° 2 θ) and d-spacings for form IV are provided in table 4 below. The XRPD peak locations marked "(U)" in table 4 are unique to form IV. For example, peaks at 8.61, 17.04, and 23.28 ° 2 Θ ± 0.2, 0.1, 0.05, or 0.01 ° 2 Θ are unique to form IV.

TABLE 4 characteristic XRPD peaks (expressed in degrees 2 θ) for form IV of SNAC

Form IV can be prepared by heating form I, II, IH, V, or VI of SNAC, or a mixture thereof, at a temperature of about 110 or 150 ℃ to the melting point of SNAC for a time sufficient to form IV. For example, form II of SNAC can be heated (such as in a drying oven) above the transition temperature of the desolvated material but below the melting temperature of SNAC (e.g., dehydration from about 130 ℃ C. to about 140 ℃ C. at a heating rate of 10 ℃ C./minute) until form IV is formed (e.g., 7 hours). After formation, form IV can be cooled and recovered.

The invention also provides a pharmaceutical composition comprising form IV of SNAC, wherein at least 50, 60, 70, 80 or 90% of the SNAC is crystalline (based on 100% by weight of SNAC).

Methanol-water co-solvate of form V SNAC

Crystalline polymorph form V of SNAC is a methanol-water co-solvate (about 0.8 moles of methanol and 2 moles of water per 1 mole of SNAC). Form V has a melting point onset of about 197 ℃ according to Differential Scanning Calorimetry (DSC) (see fig. 22). Form V of SNAC has an XRPD pattern substantially the same as shown in figure 21. Characteristic XRPD peak locations (expressed in degrees 2 θ ± 0.2, 0.1, 0.05, or 0.01 ° 2 θ) and d-spacings for form V are provided in table 5 below. The XRPD peak locations marked "(U)" in table 5 are unique to form V. For example, peaks at 6.59, 9.96, 10.86, 13.87, 17.29, and 19.92 ° 2 Θ ± 0.2, 0.1, 0.05, or 0.01 ° 2 Θ are unique to form V.

TABLE 5 characteristic XRPD peaks (expressed in degrees 2 θ) for form V of SNAC

Form V can be prepared by crystallizing SNAC (e.g., forms I-IV or VI of SNAC or mixtures thereof (e.g., mixtures of forms I and III)) from a methanol solution at a relative humidity of at least about 30, 40, or 50%. Preferably, the methanol solution is substantially free or completely free of water. For example, form V can be prepared by preparing a saturated solution of SNAC (e.g., form I-IV or VI of SNAC, or a mixture thereof) in methanol at a relative humidity of at least about 30, 40, or 50% and cooling the solution to, for example, room temperature or below (such as in an ice bath). The resulting precipitate may be filtered and dried.

Form V can also be prepared by equilibrating forms I-IV or VI of SNAC with methanol. Preferably, the methanol is substantially or completely free of water. Form V may be prepared, for example, by stirring any of forms I-IV or VI or mixtures thereof in methanol to a slurry at a relative humidity of at least 30, 40, or 50% (e.g., resulting in SNAC precipitates that precipitate out of solution) and maintaining the slurry mixture at ambient temperature for a time sufficient to form V (e.g., several days). It is preferred to use an excess of methanol (i.e., a molar ratio of methanol to SNAC greater than 1). For example, the resulting solid can be recovered by vacuum filtration and air drying.

Ethanol-water co-solvate of form VI SNAC

Crystalline polymorph form VI of SNAC is an ethanol-water co-solvate (about 0.6 moles of ethanol and 2 moles of water per 1 mole of SNAC). Form VI has a melting point onset of about 197 ℃ according to Differential Scanning Calorimetry (DSC) (see fig. 27). Form VI of SNAC has an XRPD pattern substantially the same as shown in figure 26. Characteristic XRPD peak locations (expressed in degrees 2 θ ± 0.2, 0.1, 0.05, or 0.01 ° 2 θ) and d-spacings for form VI are provided in table 6 below. The XRPD peak locations marked "(U)" in table 6 are unique to form VI. For example, peaks at 9.60, 10.43, 12.68, and 16.58 ° 2 Θ ± 0.2, 0.1, 0.05, or 0.01 ° 2 Θ are unique to form VI.

TABLE 6 characteristic XRPD peaks (expressed in degrees 2 θ) for form VI of SNAC

Form VI may be prepared by crystallizing SNAC (e.g., form I-V of SNAC or mixtures thereof) from an ethanol solution at a relative humidity of at least about 30, 40, or 50%. For example, form VI can be prepared by preparing a saturated solution of SNAC (e.g., form I-V of SNAC, or a mixture thereof) in ethanol at a relative humidity of at least about 30, 40, or 50% and cooling the solution, e.g., to room temperature or below (such as in an ice bath). The resulting precipitate may be filtered and dried.

Form VI may also be prepared by stirring forms I-V into a slurry in ethanol at a relative humidity of at least about 10, 20, or 30%. For example, form VI can be prepared by adding any of forms I-V to ethanol to form a precipitate and maintaining the slurried mixture at ambient temperature for a time sufficient to form VI (e.g., 7 days). For example, the resulting solid can be recovered by vacuum filtration and air drying.

Amorphous form of SNAC

Amorphous SNAC is unstable at ambient conditions and converts to form III upon exposure to moisture. Amorphous SNAC can be prepared by dehydrating form III of SNAC (e.g., in vacuo) for a time sufficient to form amorphous SNAC. Amorphous SNAC can also be prepared by dehydrating form V or VI of SNAC (e.g., in vacuo) for a time sufficient to form amorphous SNAC.

The crystals prepared by any of the above methods may be recovered by any method known in the art.

Active agent

Active agents suitable for use in the present invention include biologically and chemically active agents, including (but not limited to) pesticides, pharmaceutically active agents and therapeutic agents.

Suitable biologically and chemically active agents include (but are not limited to): a protein; a polypeptide; a peptide; a hormone; polysaccharides, mucopolysaccharides and specific mixtures of mucopolysaccharides; a carbohydrate; a lipid; polar organic small molecules (i.e., polar organic molecules having a molecular weight of 500 daltons or less); other organic compounds; and specific compounds which are not themselves susceptible to cleavage by the gastrointestinal mucosa (only by part of the administered dose) and/or by the activity of acids and enzymes in the gastrointestinal tract; or any combination thereof.

Other examples of suitable bioactive agents include, but are not limited to, the following: including their synthetic, natural or recombinant sources: growth hormones, including human growth hormone (hGH), recombinant human growth hormone (rhGH), bovine growth (hGH), bovine growth hormone, and porcine growth hormone; growth hormone releasing hormone; growth hormone releasing factor (e.g., GRF analog g); interferons, including α, β, and γ; interleukin 1; interleukin 2; insulin, including porcine, bovine, human and human recombinant insulin, optionally with counterions including zinc, sodium, calcium and ammonium; insulin-like growth factors including IGF-l; heparin, including unfractionated heparin, heparin analogs, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, and ultra low molecular weight heparin; calcitonin, including salmon, eel, pig and human calcitonin; erythropoietin; atrial natriuretic peptide; an antigen; a monoclonal antibody; a somatostatin; a protease inhibitor; corticotropin, gonadotropin releasing hormone; oxytocin; luteinizing hormone-releasing hormone; an egg cell stimulating hormone; glucocerebrosidase; thrombopoietin; filgrastim; prostaglandins; cyclosporine; a vasopressin; cromolyn sodium (sodium or disodium cromoglycate); vancomycin; desferrioxamine (DFO); bisphosphonates, including ibandronate, alendronate, tiludronate, etidronate, clodronate, pamidronate, olpadronate and incadronate and pharmaceutically acceptable salts thereof (e.g., ibandronate sodium); gallium salts (such as gallium nitrate, gallium nitrate nonahydrate, and gallium maltolate); acyclovir and pharmaceutically acceptable salts thereof (e.g., sodium acyclovir); parathyroid hormone (PTH), including fragments thereof; anti-migraine agents, such as BIBN-4096BS and other calcitonin gene-related protein antagonists; antimicrobial agents, including antibiotics (including bactericidal, lipopeptide and cyclopeptide antibiotics that act on gram-positive bacteria, including daptomycin), antibacterial and antifungal agents; a vitamin; analogs, fragments, mimetics, or polyethylene glycol (PEG) modified derivatives of these compounds; or any combination thereof.

According to one embodiment, the active agent is ibandronate or a pharmaceutically acceptable salt thereof (e.g., sodium ibandronate). According to another embodiment, the active agent is a gallium salt, such as gallium nitrate or gallium nitrate nonahydrate. According to another embodiment, the active agent is acyclovir or a pharmaceutically acceptable salt thereof (e.g., sodium acyclovir). According to another embodiment, the active agent is heparin. According to another embodiment, the active agent is insulin.

Pharmaceutical composition

Pharmaceutical compositions in solid form are preferred and they can be formulated into solid dosage forms. The solid dosage form may be a capsule, tablet or granule, such as a powder or sachet. The powder may be in a sachet that is mixed with the liquid and applied. Solid dosage forms may also be topical delivery systems, such as ointments, creams or semisolids. Contemplated solid dosage forms may include sustained or controlled release systems. Preferably the solid dosage form is a dosage form for oral administration.

The powders may be packaged in capsules or compressed into tablets, used in powder form or incorporated into ointments, creams or semisolids. Methods for forming solid dosage forms are well known in the art.

The amount of delivery agent in the solid dosage form is a delivery effective amount and can be determined by methods well known to those skilled in the art for any particular compound or biologically or chemically active agent.

Following administration, the active agent in the unit dosage form is absorbed into the circulation. The bioavailability of an active agent is readily assessed by measuring known pharmacological activity in the blood, such as increased clotting time caused by heparin or decreased circulating levels of calcium caused by calcitonin. Alternatively, the circulating level of the active agent itself may be measured directly.

The solid dosage form may include pharmaceutically acceptable additives such as excipients, carriers, diluents, stabilizers, plasticizers, binders, glidants, disintegrants, fillers, lubricants, plasticizers, colorants, film formers, flavoring agents, preservatives, delivery vehicles, surfactants, and any combination thereof. Preferably these additives are pharmaceutically acceptable additives such as those described in The Science and Practice of Pharmacy of Remington, (Gennaro, a.r., eds., 19 th edition, 1995, Mack pub.co.), which is incorporated herein by reference.

Suitable binders include, but are not limited to, starch, gelatin, sugars such as sucrose, molasses and lactose, calcium dihydrogen phosphate dihydrate, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyethylene glycol, ethylcellulose and waxes.

Suitable glidants include, but are not limited to, talc and silicon dioxide (silicon dioxide) (e.g., fumed silica and colloidal silica).

Suitable disintegrants include, but are not limited to, starch, sodium starch glycolate, croscarmellose sodium, crospovidone, clays, celluloses (such as purified cellulose, methylcellulose, sodium carboxymethylcellulose), alginates, pregelatinized corn starch, and gums (such as agar, locust bean gum, karaya gum, pectin, and tragacanth). A preferred disintegrant is sodium starch glycolate.

Suitable fillers include, but are not limited to, starch (such as rice starch), microcrystalline cellulose, lactose (e.g., lactose monohydrate), sucrose, glucose, mannitol, calcium sulfate, dicalcium sulfate and tricalcium sulfate.

Suitable lubricants include, but are not limited to, stearic acid, stearates (such as calcium stearate and magnesium stearate), talc, boric acid, sodium benzoate, sodium acetate, sodium fumarate, sodium chloride, polyethylene glycol, hydrogenated cottonseed oil, and castor oil.

Suitable surfactants include, but are not limited to, sodium lauryl sulfate, hydroxylated soy lecithin, polysorbates, and block copolymers of propylene oxide and ethylene oxide.

Delivery system

The amount of active agent used in the pharmaceutical compositions of the present invention is an effective amount to achieve the purpose of the active agent for the target indication. The active agent is generally employed in the composition in a pharmacologically, biologically, therapeutically or chemically effective amount. However, the amount may be lower than when the composition is used in a unit dosage form, as the unit dosage form may contain multiple delivery agent compounds/active agent compositions or may contain fractionated pharmacologically, biologically, therapeutically or actively effective amounts. The total effective amount can be administered in cumulative units that collectively contain an effective amount of the active agent.

The total amount of active agent used can be determined by methods well known to those skilled in the art. However, because the compositions of the present invention can deliver the active agent more effectively than other compositions or compositions containing the active agent alone, lower amounts of biologically or chemically active agent than are used in existing unit dosage forms or delivery systems can be administered to a subject while still achieving the same blood levels and/or therapeutic effect.

Generally, the weight ratio of delivery agent to active agent ranges from about 1: 1 to about 300: 1. This weight ratio will vary depending on the active agent and the particular indication for which it is administered.

The disclosed delivery agents facilitate the delivery of biologically and chemically active agents, particularly oral, sublingual, buccal, intraduodenal, intracolonic, rectal, vaginal, mucosal, pulmonary, intranasal, and ocular systems.

The compounds and compositions of the present invention are useful for administering biologically or chemically active agents to any animal, including (but not limited to): birds, such as chickens; mammals, such as rodents, cows, pigs, dogs, cats, primates, and particularly humans; and insects.

These compounds and compositions are particularly advantageous for the delivery of chemically or biologically active agents that might otherwise be destroyed or reduced in activity by the time the agent reaches the target area (i.e., the area from which the active agent of the delivery composition is released) and before it reaches the area encountered. In particular, the compounds and compositions of the present invention are useful for oral administration of active agents, especially those that are not commonly delivered by oral administration or those for which enhanced delivery is desired.

Compositions comprising the compounds and active agents have utility in delivering the active agent to a selected biological system and increasing or enhancing the bioavailability of the active agent over delivery of the active agent without the use of a delivery agent. Delivery may be improved by delivering more active agent over a period of time or delivering the active agent over a particular period of time (such as faster acting or delayed delivery) or over a period of time (such as sustained delivery).

Another embodiment of the invention is a method of treating or preventing a disease or achieving a desired physiological effect (such as those listed in the table below) in an animal by administering a composition of the invention to the animal. Specific indications of active agents can be found in the Physicians' Desk Reference (54 th edition, 2000, Medical Economics Company, inc., Montvale, NJ), which is incorporated herein by Reference. The active agents in the following table include analogs, fragments, mimetics, and polyethylene glycol modified derivatives thereof.

The following examples illustrate the invention but are not intended to be limiting. All percentages are by weight unless otherwise indicated.

DSC

The melting point was determined by Differential Scanning Calorimetry (DSC). The quoted values were obtained using Perkin Elmer Pyris 1 software for Windows. The instrument temperature was calibrated using the melting points of indium and zinc and the enthalpy of the instrument was calibrated using the melting enthalpy of indium. Calibration checks were performed based on conventional methods using indium standards. The sample was sealed in an aluminum pan with a crimped lid with small holes. The sample was then heated from 30 ℃ to 250 ℃ in a nitrogen environment at 10 ℃/min. The unground sample was lightly ground with a mortar and pestle prior to analysis to improve thermal contact with the sample disk surface.

XRPD

Powder X-ray diffraction analysis was performed using a Shimadzu XRD-6000 powder diffractometer from Shimadzu Scientific Instruments, Inc. of Colu mbia, Md. The instrument was calibrated using silicon powder and the calibration was correct when tested using NIST #675 low angle diffraction standards. Using Cu Ka irradiationThe sample is irradiated. The unground sample was lightly ground with a mortar and pestle so that a sample with a smooth, uniform surface for analysis could be prepared. Diffraction patterns between 2-40 ° 2 θ were used as fingerprint regions to identify the crystal structure present in the batch.

Thermogravimetric analysis (TGA)

Thermogravimetric analysis of 4-CNAB sodium was performed using a Perkin-Elmer TGA7 thermogravimetric analyzer with Pyris 1 for Windows software. The instrument temperature was calibrated using the curie point of allumel (alumel) alloy and nickel. The sample was heated from 30 ℃ to 300 ℃ in a nitrogen environment and the percent weight change was recorded as a function of temperature. The unground batch was lightly ground using a mortar and pestle prior to analysis in order to reduce the effect of particle size and improve contact with the inner surface of the platinum sample holder.

Water adsorption-desorption behavior

Adsorption analysis was performed using a vapor adsorption analyzer (available from VTI Corporation of Hialeah, Florida). The instrument was calibrated using PVP and NaCl. The sample (non-solvate) was dried to constant weight at 60 ℃ before analysis. The solvate samples were not dried prior to testing. The equilibrium water content from samples at 5% Relative Humidity (RH) -95% RH and then returned to 5% RH was determined at 25 ℃.

FTIR

FTIR was performed on a Perkin Elmer Spectrum BX FT-IR using a KBr dish. 1mg of the sample was dispersed in 150mg of KBr. Resolution was 4cm^-1And the average of 32 scans was calculated.

Example 1

Preparation of form I of SNAC

Form I of SNAC was prepared as follows. The free acid of SNAC (i.e., N- (8- [ 2-hydroxybenzoyl ] amino) octanoic acid) is prepared by the method described in example 1 of international publication No. WO 00/59863, which is incorporated herein by reference in its entirety, using the appropriate starting materials.

Form I of SNAC was prepared from the free acid of SNAC by the following method also described in international publication No. WO 00/59863, example 12.

To a clean 300 gallon reactor was added 321L ethanol denatured with 0.5% toluene. 109kg (dry) of SNAC free acid was added while stirring. The reactor was heated to 28 ℃ and maintained at a temperature above 25 ℃. A solution of 34L of pure water, USP and 15.78kg of sodium hydroxide was prepared, cooled to 24 ℃ and added to the stirred reactor over 15 minutes, maintaining the reaction temperature at 25-35 ℃. The mixture was stirred for a further 15 minutes.

To the adjacent reactor was added 321L ethanol denatured with 0.5% toluene. The reactor was heated to 28 ℃ using a circulator. The solution from the first reactor was added to the second reactor over 30 minutes, maintaining the temperature above 25 ℃. The contents were stirred and 418L heptane was added. The reaction mixture was cooled to 10 ℃, centrifuged, and washed with 60L heptane. The product was collected and dried in a Stokes oven at 82 ℃ and 26 "Hg vacuum for about 65 hours (within 1 week). 107.5kg of SNAC monosodium salt (i.e., monosodium salt of N- (8- [ 2-hydroxybenzoyl ] -amino) caprylic acid) was recovered.

XRPD, DSC, TGA, FTIR and adsorption/desorption spectra of form I are shown in figures 1-5, respectively.

Example 2

Preparation of form II of SNAC:

form II of SNAC was prepared as follows. The process of example 1 was repeated, but without the final drying step. The SNAC ethanol solvate obtained was then dried in a drum dryer and agglomerated (formed into pellets). The dryer does not contain an internal stirring device. Taking out SNAC from drum dryerA grinder (Quadro engineering inc. from Waterloo, Ontario, Canada) grinds and dries the trays. SNAC was stored in a double-lined polyethylene bag in a stainless steel drum for at least 3 years.

XRPD, DSC, TGA, FTIR and adsorption/desorption spectra of form II are shown in figures 6-10, respectively.

Example 3

Preparation of form III of SNAC:

form III is prepared by exposing form I of SNAC to a 90% relative humidity environment until form I is not detectable by XRPD. The material was then dried in a hood to a moisture content of about 15% w/w.

XRPD, DSC, TGA, FTIR, and adsorption/desorption spectra of form III are shown in fig. 11-15, respectively.

Example 4

Preparation of form IV of SNAC:

form IV was prepared by heating form II in a hot air drying oven at 170 ℃ for 3 hours. Form IV was prepared according to DSC with a melting point onset of about 198 ℃ and XRPD, DSC, TGA, FTIR and adsorption/desorption spectra are shown in figures 16-20.

Example 5

Preparation of form V of SNAC:

form V of SNAC was prepared by stirring form I of SNAC into a slurry in methanol over 1 week. The resulting precipitate was filtered and air-dried for 1 hour. Form V was prepared according to DSC with a melting point onset of about 197 ℃ and XRPD, DSC, TGA, FTIR and adsorption/desorption spectra are shown in figures 21-25.

Example 6

Process for preparing form VI of SNAC

Form VI of SNAC was prepared by stirring form I of SNAC into a slurry in ethanol over 1 week. The resulting precipitate was filtered and air-dried for 1 hour. Form VI was prepared according to DSC with a melting point onset of about 197 ℃, and XRPD, DSC, TGA, FTIR, and adsorption/desorption spectra are shown in figures 26-30.

Example 7

Preparation of capsules containing form I or III of SNAC and heparin USP

Capsules (No. 1, available from Capsugel of Morris Plains, NJ) containing SNAC (form I or III) and heparin USP (30,000IU) as shown in table 7 were prepared as follows. SNAC (form I or III prepared as in examples 1 and 3) and heparin were screened through #35 mesh. Specific amounts of heparin and SNAC were weighed and transferred to clean and dry 8oz glass mortar. SNAC equal to the heparin volume was added to the mortar and mixed for 2 minutes using a pestle. The remainder of the SNAC was added to the mixture and mixed for an additional 2 minutes. Filling into capsule containing appropriate amount of the above materials.

TABLE 7

¹One presumption is that form III of SNAC is a trihydrate, with about 15.62% (28.39mg) of form III being water and the remainder 84.38% (153.33mg) being SNAC (on a water-free basis).

Applied to cynomolgus monkey

Cynomolgus monkeys (average male weight 4.1kg and average female weight 3.0kg) were fasted for at least 24 hours prior to dosing. 3 SNAC/heparin capsules were inserted on the catheter tip and the capsules were expelled into the stomach by ventilation. Food was restored 2 hours after dosing. Water was available at all times. Approximately 1.3ml of whole blood was collected into citrate containing tubes before and at 10, 20, 30 and 50 minutes and 1, 1.5, 2, 3, 4 and 6 hours after dosing. Blood samples were centrifuged at 2500RPM for 10 minutes and 250L of the resulting plasma was used for factor Xa determination using an Organon Teknika COAG-A-MATE MTX/MTX II machine. The standard range for this assay is 0-2IU/mL heparin.

The results for form I and III of SNAC and heparin are shown in figures 31 and 32, respectively. Results were averaged for monkeys of different sex and weight. In other words, there are data points for 4 monkeys (3.9kg male, 4.2kg male, 3.2kg female and 2.9kg female). The results for each SNAC form at each time point were averaged for all monkeys and are shown in figure 33.

Example 8

Preparation of capsules containing form I or III of SNAC and heparin USP

Capsules (No. 1, available from Capsugel of Morris Plains, NJ) containing SNAC (form I or III) and heparin USP (30,000IU) as shown in table 7 were prepared by the method described in example 7.

Applied to cynomolgus monkey

The method described in example 7 was repeated using 2 male monkeys with an average weight of 5.6kg and 2 female monkeys with an average weight of 6.9 kg.

The results for form I and III of SNAC and heparin are shown in figures 34 and 35, respectively. Results were averaged for monkeys of different sex and weight. In other words, there are data points for 4 monkeys (5.7kg male, 5.6kg male, 7.6kg female and 6.3kg female). The results for each SNAC form at each time point were averaged for all monkeys and are shown in figure 36.

Example 9

The intrinsic dissolution rates of forms I-IV of SNAC as prepared in examples 1-4 were determined as follows.

The intrinsic dissolution rates of the crystalline form I-IV particles were determined using a Wood's instrument. Pellets of form I, II, III or IV of 300mg SNAC were prepared in a mold. The surface area of the pellets available for the dissolution medium was 0.484 cm. The granules were compressed into disks on a Carver press at 1200 and 1400 lbs. The mold was then attached to the handle of the dissolution apparatus. The mold was rotated at 50rpm and then immersed in 900mL of degassed dissolution medium (pH 6.3) maintained at 37 ℃. Dissolution experiments were performed in water and in triplicate. The samples were analyzed by UV spectroscopy at 297.5nm on line. The intrinsic dissolution rate is determined from the initial linear portion of the dissolution profile under immersion conditions.

The results are shown in FIGS. 37 and 38. The calculated dissolution rates for forms I-IV are shown in table 8 below.

TABLE 8

Example 10

The solubility of each of forms I-IV of SNAC in acetonitrile was determined at ambient humidity and 25 ℃. Acetonitrile was chosen as the solvent because it is one of several solvents in which SNAC is relatively poorly soluble, and the solution can approach infinite dilution. The solubility data is shown in table 9 below.

TABLE 9

Example 11

The effect of milling on form I of SNAC was determined as follows. The milling was carried out in a ball mill. Samples were taken after 20 hours and analyzed by XRPD.

The XRPD patterns of the SNAC samples before and after ball milling were essentially the same as shown in figure 39.

Example 12

The effect of wet granulation on form I of SNAC was determined as follows. Form I of SNAC was hand wet granulated in a glass mortar using a pestle with the addition of 20% w/w water. Wet particles were analyzed by XRPD.

The XRPD patterns of the SNAC samples before and after wet granulation are shown in figure 40. The sample after wet granulation exhibited an XRPD pattern substantially the same as form III.

Example 13

The effect of compression on forms I and III of SNAC was evaluated as follows. Approximately 300mg samples were each compacted on a Carver press using 4500lb of force and 1 minute retention time. The press cycle was repeated 20 times. The compositions were analyzed by XRPD for crystalline forms of SNAC.

The results for forms I and III are shown in figures 41 and 42, respectively. As shown by these figures, the crystalline form in both samples was essentially unchanged.

Example 14

Preparation of amorphous SNAC

Amorphous form was prepared by drying form III in a vacuum oven at 25 ℃ and 0.3in. The dried material was a mixture of amorphous form and about 10% of SNAC starting form III. Longer drying and higher vacuum may produce substantially pure and pure amorphous form.

XRPD, DSC, TGA, FTIR, and adsorption/desorption spectra of amorphous SNAC containing about 10% of form III are shown in fig. 43-47, respectively.

All patents, applications, articles, publications and test methods mentioned above are incorporated herein by reference.

Claims (14)

1. A methanol-water co-solvate of monosodium N- [8- (2-hydroxybenzoyl) amino ] caprylate exhibiting an X-ray powder diffraction pattern substantially as shown in figure 21.
2. A methanol-water co-solvate of monosodium N- [8- (2-hydroxybenzoyl) amino ] caprylate exhibiting an X-ray powder diffraction pattern having peaks expressed in degrees 2 Θ ± 0.2 ° 2 Θ at 6.24, 6.59, 9.96, 10.86, 13.87, 16.35, 17.29, 18.99, 19.92, 20.44, 21.35, 22.68, 22.92, 24.16, 24.64, 25.04, 26.13, 30.20, 30.48, 31.52, 32.13, 33.03, 34.04, 35.44, 35.64, 35.92, 36.49, 37.50, and 39.03.
3. 3. The methanol-water co-solvate of claim 2, wherein the methanol-water co-solvate has a melting point onset at 197 ℃ as determined by differential scanning calorimetry.
4. 4. A process for the preparation of a methanol-water co-solvate of monosodium N- [8- (2-hydroxybenzoyl) amino ] caprylate of claim 1 or 2 comprising the step of crystallizing monosodium N- [8- (2-hydroxybenzoyl) amino ] caprylate from a methanol solution at a relative humidity of at least 30%.
5. 5. The method of claim 4, wherein the methanol solution is substantially free of water.
6. 6. A process for the preparation of a methanol-water co-solvate of monosodium N- [8- (2-hydroxybenzoyl) amino ] caprylate of claim 1 or 2 comprising the step of equilibrating crystalline forms I-IV or VI of monosodium N- [8- (2-hydroxybenzoyl) amino ] caprylate with methanol, wherein

   Form I exhibits an X-ray powder diffraction pattern having peaks, expressed in degrees 2 Θ ± 0.2 ° 2 Θ, at 2.98, 5.85, 8.66, 11.56, 14.53, 15.72, 18.88, 22.12, 26.36, and 30.88;

   form II exhibits an X-ray powder diffraction pattern having peaks, expressed in degrees 2 Θ ± 0.2 ° 2 Θ, at 3.29, 5.78, 6.56, 8.76, 11.53, 11.96, 14.47, 17.12, 17.76, 18.08, 18.76, 19.44, 20.16, 20.72, 21.12, 21.84, 22.48, 23.44, 23.96, 24.56, 25.16, 25.40, 26.20, 26.48, 26.88, 27.73, 28.95, 30.12, 30.69, 31.57, 32.76, 34.99, and 37.98;

   form III exhibits an X-ray powder diffraction pattern having peaks, expressed in degrees 2 Θ ± 0.2 ° 2 Θ, at 6.69, 11.31, 13.58, 16.41, 16.80, 17.91, 19.40, 19.92, 20.16, 20.56, 21.32, 21.60, 23.56, 24.84, 26.13, 28.80, and 30.01;

   form IV exhibits an X-ray powder diffraction pattern having peaks, expressed in degrees 2 Θ ± 0.2 ° 2 Θ, at 3.16, 5.89, 6.32, 8.61, 11.55, 14.45, 17.04, 18.92, 20.80, 21.16, 22.36, 23.28, and 23.76; and

   form VI exhibits an X-ray powder diffraction pattern with peaks at 5.68, 6.35, 6.72, 9.60, 10.43, 11.31, 12.68, 14.95, 16.58, 17.46, 18.12, 18.96, 19.37, 19.88, 20.95, 21.54, 22.08, 22.36, 22.95, 23.76, 24.24, 25.08, 25.56, 26.98, 27.36, 28.68, 29.35, 30.48, 30.84, 31.91, 34.00, 36.16, and 38.32 expressed in degrees 2 θ ± 0.2 ° 2 θ.
7. 7. The process of claim 6, wherein the equilibration is in the absence of water.
8. 8. A process for the preparation of a methanol-water co-solvate of monosodium N- [8- (2-hydroxybenzoyl) amino ] caprylate of claim 1 or 2 comprising the steps of: slurrying any one of crystalline forms I-IV or VI of monosodium N- [8- (2-hydroxybenzoyl) amino ] caprylate or mixtures thereof in methanol at a relative humidity of at least 30% and maintaining the slurried mixture at ambient temperature for a sufficient time to form the methanol-water co-solvate, wherein

   Form I exhibits an X-ray powder diffraction pattern having peaks, expressed in degrees 2 Θ ± 0.2 ° 2 Θ, at 2.98, 5.85, 8.66, 11.56, 14.53, 15.72, 18.88, 22.12, 26.36, and 30.88;

   form II exhibits an X-ray powder diffraction pattern having peaks, expressed in degrees 2 Θ ± 0.2 ° 2 Θ, at 3.29, 5.78, 6.56, 8.76, 11.53, 11.96, 14.47, 17.12, 17.76, 18.08, 18.76, 19.44, 20.16, 20.72, 21.12, 21.84, 22.48, 23.44, 23.96, 24.56, 25.16, 25.40, 26.20, 26.48, 26.88, 27.73, 28.95, 30.12, 30.69, 31.57, 32.76, 34.99, and 37.98;

   form III exhibits an X-ray powder diffraction pattern having peaks, expressed in degrees 2 Θ ± 0.2 ° 2 Θ, at 6.69, 11.31, 13.58, 16.41, 16.80, 17.91, 19.40, 19.92, 20.16, 20.56, 21.32, 21.60, 23.56, 24.84, 26.13, 28.80, and 30.01;

   form IV exhibits an X-ray powder diffraction pattern having peaks, expressed in degrees 2 Θ ± 0.2 ° 2 Θ, at 3.16, 5.89, 6.32, 8.61, 11.55, 14.45, 17.04, 18.92, 20.80, 21.16, 22.36, 23.28, and 23.76; and

   form VI exhibits an X-ray powder diffraction pattern with peaks at 5.68, 6.35, 6.72, 9.60, 10.43, 11.31, 12.68, 14.95, 16.58, 17.46, 18.12, 18.96, 19.37, 19.88, 20.95, 21.54, 22.08, 22.36, 22.95, 23.76, 24.24, 25.08, 25.56, 26.98, 27.36, 28.68, 29.35, 30.48, 30.84, 31.91, 34.00, 36.16, and 38.32 expressed in degrees 2 θ ± 0.2 ° 2 θ.
9. 9. A pharmaceutical composition comprising: (A) a methanol-water co-solvate of monosodium N- [8- (2-hydroxybenzoyl) amino ] caprylate of claim 1 or 2; and (B) a bioactive agent.
10. 10. The pharmaceutical composition of claim 9, wherein the bioactive agent is heparin.
11. 11. The pharmaceutical composition of claim 9, wherein the bioactive agent is a low molecular weight heparin.
12. 12. Use of the pharmaceutical composition of any one of claims 9-11 in the manufacture of a medicament for administering a biologically active agent to an animal in need thereof.
13. 13. The use of claim 12, wherein the bioactive agent is heparin.
14. 14. A methanol-water co-solvate of monosodium N- [8- (2-hydroxybenzoyl) amino ] caprylate according to claim 1 or 2 wherein the molar ratio of methanol to water to monosodium N- [8- (2-hydroxybenzoyl) amino ] caprylate is 0.8: 2: 1.