MXPA05009564A - Weak base salts. - Google Patents

Abstract

Pharmaceutical compositions comprising a salt of a weak base compound of formula: wherein X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 4; Y is hydrogen, chlorine, nitro, methyl, ethyl or oxychloro; R is hydrogen, alkylaminocarbonyl wherein the alkyl group has from 3 to 6 carbon atoms or an alkyl group having from 1 to 8 carbons and R2 is 4-thiazolyl, NHCOOR1 wherein R, is aliphatic hydrocarbon of less than 7 carbon atoms, or an alkyl group of less than 7 carbon atoms; one or more free acids; and optional pharmaceutical additives are provided.

Description

SALES OF WEAK BASES BACKGROUND OF THE INVENTION The most active pharmaceutical ingredients are unsatisfactorily soluble in water and, therefore, provide a challenge for formulators in the development of a therapeutically viable formulation. A variety of solubilization techniques have been described that include the modification of either the solute or the solvent to overcome this challenge. If a compound has an ionization center, then there is the possibility of forming a salt. The formation of salts provides a means to alter the physicochemical and biological characteristics resulting from a drug without modifying its chemical structure. Factors that can be changed by salt formation include solubility, dissolution, hygroscopicity, taste, physical and chemical stability and polymorphism. The water-soluble salts allow the preparation of aqueous, sterile, injectable solutions and rapid dissolution of the active component contained in the solid dosage form. This invention is in the field of improving the water solubility of benzimidazole derivatives and other weak bases and the provision of pharmaceutical formulations thereof. The derivatives of REF: 166062 Benzimidazole are useful for inhibiting the growth of cancers, tumors and viruses in mammals, particularly in humans and warm-blooded animals (U.S. Patent Nos. 6,479,526, 5,880,144, 6,245,789, 5,767,138, 6,265,437). It has been reported that certain benzimidazole derivatives used in combination with other compounds are useful as fungicides (U.S. Patent Nos. 3,954,993, 4,593,040, 5,756,500, 4,835,169, 4,980,346). However, the benzimidazole derivatives, including carbendazim, are unsatisfactorily soluble in water. The oral, projected dose of carbendazim for cancer treatment is up to several hundred mg a day, which is much larger than its solubility in water. Other weak bases suffer from the same unsatisfactory water solubility. There is a need for improved formulations of benzimidazole derivatives and other weak bases. BRIEF DESCRIPTION OF THE INVENTION We provide weak base salts having the formula: wherein X is hydrogen, halogen, alkyl with less than 7 carbon atoms or alkoxy with less than 7 carbon atoms; n is an integer, positive less than 4; And it is hydrogen, chlorine, nitro, methyl, ethyl or oxychlor; R is hydrogen, alkylaminocarbonyl, wherein the alkyl group has from 3 to 6 carbon atoms or an alkyl group having from 1 to 8 carbon atoms, and R2 is 4-thiazolyl, NHGOQRi, wherein Rx is an aliphatic hydrocarbon with less than 7 carbon atoms or an alkyl group with less than 7 carbon atoms. The salt is preferably one or more selected from the group consisting of: chlorides, bromides, phosphates, sulfates, tosylates, benzoylates, nitrates, sulfonates, formates, tartrates, maleates, maleates, citrates, benzoates, salicylates, ascorbates and mesylates. Each salt comprising a weak base cation and individual anions and all groups and subgroups of anions are particular embodiments of the invention. Also provided are pharmaceutical compositions comprising a salt of a weak base compound of the formula: wherein X is hydrogen, halogen, alkyl with less than 7 carbon atoms or alkoxy with less than 7 carbon atoms; n is an integer, positive less than 4; And it is hydrogen, chlorine, nitro, methyl, ethyl or oxychlor; R is hydrogen, alkylaminocarbonyl, wherein the alkyl group has 3 to 6 carbon atoms or an alkyl group having 1 to 8 carbon atoms and R2 is 4-thiazolyl, NHCOORÍ, where ¾. is an aliphatic hydrocarbon with less than 7 carbon atoms, or an alkyl group with less than 7 carbon atoms; one or more free acids; and pharmaceutical additives, optional. In particular embodiments, the salt and free acids are present in the composition in a ratio of about 1: 0.5 to about 1: 3 by weight. All individual values and ranges of relationships are included in this text, including approximately 1: 1 and approximately 1: 2. Methods for making and using the salts and compositions described in this text are also provided. Compositions consisting essentially of the components described in this text are also included. Also provided are methods for treating a disease comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a salt of a weak base compound of the formula: wherein X is hydrogen, halogen, alkyl with less than 7 carbon atoms or alkoxy with less than 7 carbon atoms; n is an integer, positive less than 4; And it is hydrogen, chlorine, nitro, methyl, ethyl or oxychlor; R is hydrogen, alkylaminocarbonyl, wherein the alkyl group has from 3 to 6 carbon atoms or an alkyl group having from 1 to 8 carbon atoms and R2 is 4-thiazolyl, NHCOORi, wherein Ri is an aliphatic hydrocarbon with less than 7 carbon atoms; carbon, or an alkyl group with less than 7 carbon atoms; one or more free acids; and pharmaceutical additives, optional. In particular pharmaceutical compositions, the salt and free acid are present in the composition in a ratio of about 1: 0.5 to about 1: 3 by weight. Other relationships described in this text are also included. As used in this text, "free acid" means a composition that is ionized in water to form hydrogen bonding and an anion. In certain compositions of the invention, the free acid contains the same anion as the salt. In certain compositions of the invention, the free acid contains one or more anions, one of which may be the same anion as that in the salt. As used in this text, "salt" means a composition that is ionized in water to form an anion and a cation. In the salts of the invention, the weak base provides the cation in the salt. As used in this text, "weak base" or "weak bases" are those compounds that have a value pKa less than about 7. Weak bases include prodrugs of weak bases. Preferred weak bases have a pKa value less than about 5. Other preferred weak bases have a pKa value less than about 4. Weak bases having pKa values less than about 7 and compounds in all ranges of pKa values less than about 7 are included in the invention. Some kinds of weak bases include: imidazole derivatives having a pKa value less than about 7, pyridine derivatives having a pKa value of less than about 7, aniline derivatives having a pKa value of less than about 7, and compounds containing combinations thereof having a pKa value of less than about 7. The imidazole derivatives are defined as compounds that include the structure: Some preferred imidazole derivatives include the following: Compound pKa Cimetadine 6.3 Gliodine ~ 7 Miconazole 6.7 Pyridine derivatives are defined as compounds that include the structure: Some preferred pyridine derivatives include the following: Compues or pKa Nicotinamide 3.4 Niquetamide 3.5 Aniline derivatives are defined as compounds that include the structure: where R is hydrogen or alkyl having from 1 to 7 carbon atoms. The aromatic ring may have other substituents, as is known in the art. Some preferred aniline derivatives include the following: Compound pKa BPÜ NSC 639829 ~ 5 ???? 4 Mxnioxadil 4.6 Benzocaione 2.5 Butambeno 5.4 A class of xmxdazol derivatives xncludes those with the formula: where n is an integer from 1 to 3, R is hydrogen, alkyl having 1 to 7 carbon atoms, chlorine, bromine, fluoro, oxychlor, hydroxy, sulfhydryl or alkoxy having the formula -O (CH2) and ( CH3), where y is an integer from 0 to 6. A particular compound of this class is PG 300995: Another class of imidazole derivatives includes benzimidazoles and benzimidazole derivatives. As used in this text, "benzimidazoles" are those that have the formula: wherein X is hydrogen, halogen, alkyl with less than 7 carbon atoms or alkoxy with less than 7 carbon atoms; n is an integer, positive less than 4; And it is hydrogen, chlorine, nitro, methyl, ethyl or oxychlor; R is hydrogen, alkylaminocarbonyl, wherein the alkyl group has 3 to 6 carbon atoms or an alkyl group having 1 to 8 carbon atoms and R 2 is 4-thiazolyl, NHCOORi, wherein Ra is an aliphatic hydrocarbon with less of 7 carbon atoms, or an alkyl group of less than 7 carbon atoms. A preferred class of benzimidazoles are those wherein R is hydrogen. Another preferred class of benzimidazoles are: wherein R is an alkyl group of 1 to 8 carbon atoms and R 2 is selected from the group consisting of 4-thiazolyl or NHCOOORi, wherein Ri is methyl, ethyl or isopropyl and pharmaceutically acceptable acid salts thereof with both organic as well as inorganic As used herein, "benzimidazole derivatives" include benzimidazoles as defined above and benzimidazole prodrugs. The "prodrugs" are considered to be any covalently linked carrier, which releases the active, precursor drug (weak base) according to the formula of the parent drug described above in vivo when this prodrug is administered to a mammalian subject. The prodrugs of the weak bases are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in a routine manipulation or in vivo, to the precursor compounds. Prodrugs include compounds wherein the hydroxy, amine or sulfhydryl groups bind to any group which, when administered to a mammalian subject, is cleaved to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, alcohol acetate, formate or benzoate derivatives or amine functional groups in weak bases; phosphate esters, dimethylglycine esters, aminoalkylbenzyl esters, aminoalkyl esters and carboxyalkyl alcohol esters and phenol functional groups in weak bases; and similar. The compositions of the invention are useful for administration in animals, preferably mammals, and preferably humans. The compositions of the invention are administered using any form of administration and any suitable dosage that provides a pharmaceutically active dose in an animal, preferably a mammal, as is known in the art. The compositions of the present invention are used for oral administration, by injection slow intravenous or infusion, as is known in the field. Because the compositions are acidic, other forms of administration may be inadequate. If the compositions are injected, the injection rate should be decreased to avoid local irrigation, as is known in the field. The embodiments of the invention can be formulated as is known in the art and is described in WO 01/12169, U.S. Patent No. 3,903,297 and U.S. Patent No. 6,423,734, for example, all of which are incorporated by reference to the degree congruent with the present description and especially for details of the formulations. The compositions of the present invention can be administered in a unit dosage form and can be prepared by any method well known in the art without undue experimentation. These methods include combining the compositions of the present invention with a carrier or diluent that constitutes one or more pharmaceutically acceptable additives, as is known in the art without undue experimentation. The dosages of the compositions of the invention and the frequency of administration are easily determined by means known in the art without undue experimentation. Oral formulations that are suitable for use in the practice of the present invention include capsules, gels, stamps, tablets, powders or tablets effervescent or non-effervescent, powders or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion. The compositions of the present invention can also be presented as a bolus, electuary or paste. The capsules or tablets may include suitable additives that provide the desired properties, such as binding substances, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow inducing agents and melting agents, as is known in the art. The techniques and compositions for making the dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker &; Rhodes, Editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2- edition (1976). Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Macle Publishing Company, a standard reference text in the field. Useful equipment is also provided in the treatment of diseases, which comprise one or more compositions of the invention and may include instructions for administration.

"Pharmaceutically acceptable" and "non-toxic" means that it is suitable for use in humans and / or animals without side effects, adverse, undue (such as toxicity, irritation and allergic response) commensurate with a reasonable benefit / risk reaction.

"Pharmaceutically active" means that it is capable of causing a physiological change, proposed in an animal, preferably a mammal. "Pharmaceutically acceptable additives" include cosolvents, surfactants, complexing agents, hydrotropes and other components that are desired for pharmaceutical use, as is known in the art, such as carriers, preservatives, emulsifying agents, diluents, sweeteners, flavoring agents for control of viscosity, thickeners, dyes and pharmaceutically acceptable fusion agents. Any level of pharmaceutically acceptable additives and any pharmaceutically acceptable, individual additive or combination of additives can be used, so long as these additives do not reduce the solubility below a desired level or make the composition toxic, as defined above. The term "pharmaceutically acceptable carrier" is known in the art, see, for example, U.S. Patent No. 6,479,526. As used in this text, "approximately" is proposed to indicate a range caused by uncertainty experimental. When used in conjunction with salt and acid ratios, "soon" means ± 5%. As used in this text, "patient" means an animal, mammal or human. A class of patients are mammals. A class of patients are humans. BRIEF DESCRIPTION OF THE FIGURES Figures 1A-1E show microscopic images of different carbendazim salts. Figure 2 shows x-ray powder patterns for different carbendazim salts. Figure 3 shows DSC thermograms of different carbendazim salts. Figures 4A-4D show HSM photographs of carbendazim sulfate. Figure 5 shows TGA thermograms of carbendazim sulfate and carbendazim hydrochloride. Figure 6 shows an order of compaction of sulphate salt along the axis b. Figure 7 shows TGA thermograms of carbendazim hydrochloride at different heating rates. Figure 8 shows the logarithm of the heating rates versus the absolute, reciprocal temperature; ?: C = 0.0799 and 0: C = 0.05. Figures 9A-9F show an ellipsoid diagram of molecules of different carbendazim salts in the asymmetric unit in a probability of 50%, showing the atomic numbering scheme: (a) hydrochloride; (b) phosphate; (c) sulfate; (d) mesylate; (e) besilate; and (f) tosylate. The figures IOA - ??? propeller-type sorting around a binary, helical axis; a: portions of carbendazim; b: hydrochloride salt. Figure 11 shows an order of compaction of the phosphate salt along the axis c. Figure 12 shows the order of compaction of the sulfate salt along the axis b. Figure 13 shows the order of compaction of the mesylate salt along the axis b. Figure 14 shows the order of compaction of the besilate salt along the axis b. Figure 15 shows the order of compaction of tosylate against a binary axis along the axis c. Figure 16 shows the moisture adsorption curves for different carbendazim salts:?: Hydrochloride salt; x: sulfate salt; 0: tosylate salt; *: besilato salt; ?: phosphate salt; and |: mesylate salt. Figures 17A-17B show dust x-ray diffraction patterns for: (a) mesylate salt and (b) phosphate salt. Figures 18A-18B show dissolution profiles of carbendazim and its salts in (a) water and (b) 0.1N HC1; or: free base; 0: hydrochloride salt; : phosphate salt, |: sulfate salt,?: mesylate salt; ?: besilato salt; and A: tosylate salt. Figure 19 shows dissolution profiles of phosphates in water; or: free base, *: physical mixture (1: 1), x: phosphate salt and?: physical mixture (1: 2). Figure 20 shows dissolution profiles of tosylates in water; ?: tosylate salt; ?: physical, eguimolar mixture of tosylate salt - p-toluenesulfonic acid. DETAILED DESCRIPTION OF THE INVENTION The invention can be further understood by reference to the following non-limiting examples. A person of ordinary skill in the field will appreciate that all weak and acid bases different from those exemplified in particular can be used without undue experimentation. The applicant does not wish to be limited by any theory presented in this text. Synthesis Weak bases, including benzimidazole derivatives, are commercially available or can be prepared in a variety of ways well known to an expert in the field of organic synthesis without undue experimentation. The benzimidazole derivatives are synthesized using the methods described below, together with synthetic methods known in the art. organic chemistry, synthetic, or variations thereof as will be appreciated by those skilled in the field without undue experimentation. The benzimidazole derivatives can be prepared according to the method described in U.S. Patent No. 3,738,995 issued to Adams et al., June 12, 1973. Thiazolyl derivatives can be prepared according to the methods described in Brown et al. , J. Am. Chem. Soc, 83 1764 (1961) and Grenda et al., J. Org. Chem., 30, 259 (1965). Materials Carbendazim was provided by Procter & Gamble Company (Cincinnati, Ohio) and used as received. All other chemicals were of reagent quality, purchased from Sigma (St. Louis, MO) or Aldrich (St. Louis, MO) and used without further purification. Preparation of salts The main problem for the selection of salts of an ionizable drug is the consideration of the relative basicity (or acidity) of the drug and the relative strength of the conjugate acid (base). In order to form a salt, the p-value of the conjugate acid must be at least two units less than the pKa value of the basic center of the drug. Preferably, the selected counterion must possess minimal toxic effects. Carbendazim has a basic p-value of 4.5. The following anionic counterions were used for the preparation of salts: Table 1 Acid Weight in Mol Pkai Pka2 Pka3 HCI 36.46 < -6 H2S04 98.08 -3 P-Toluenesulfonic acid 172.21 -1.34 Methanesulfonic acid 96.10 -1.2 Benzenesulfonic acid 158.18 0.7 Phosphoric acid 98.0 1.96 7.12 12.32 Phosphoric acid (0.98 g) was added to 100 water stored on a heating plate maintained at 70 ° C. To this solution, then 1.92 g of carbendazim were added in portions. With the reaction to form the salt, carbendazim began the dissolution. The system was heated to favor the reaction and to increase the solubility of the salt formed. The slurry was continuously stirred at 250 rpm for about 60 minutes until a saturated solution was obtained. The saturated solution was vacuum filtered immediately using a pre-heated (70 ° C) glass filter in a conical flask that was pre-equilibrated at (70 ° C). The final filtered product was slowly cooled to room temperature by putting it back on the heating plate programmed for a decrease in temperature of 2 ° C / minute. The solution was then left at room temperature overnight, whereby the needle-shaped crystals were broken out of the solution. The crystals formed were removed from the water using a spatula and dried on filter paper to ensure evaporation of the surface water molecules. In a similar manner, other salts (hydrochloride, sulfate, tosylate and besylate) were prepared in which an equimolar amount of free acid and base was added. To synthesize the mesylate salt, the process had to be modified due to the high solubility of the free base in methanesulfonic acid. 600 mg of carbendazim was added portionwise and swirled to a solution of 2 ml of 2 M methanesulfonic acid. Then, the suspension was rotated overnight in an end-to-end rotating apparatus. Then, it was filtered and left at room temperature to evaporate slowly for 2 days, when crystals were obtained as fine needles. The crystals were separated from the solution by filtration and washed with isopropyl alcohol to remove excess methanesulfonic acid. The crystals were then air dried to ensure evaporation of the isopropyl alcohol.

Thermal Analysis The thermal analysis methods that were used included differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and hot stage microscopy (HSM), for its acronym in English) . Traces of the DSC were recorded with a TA Instruments DSC Q1000 device (TA Instruments, New Castle, DE). Samples weighing 1-3 mg were heated in folded aluminum pans at a rate of 5 ° C / minute under a nitrogen flow of 40 ml / minute. The TGA analysis was performed on all the samples that the DSC indicated as possible solvates or hydrates. The TGA traces were recorded with a TA Instruments TGA Q-50 device (TA Instruments, New Castle, DE). The weight of the samples was approximately 2 to 4 mg and heating rates of 2-15 ° C / minute were used under a nitrogen gas flow of 60 ml / minute. The HSM analysis was carried out on small amounts of the sample with a Mettler FP 82 hot stage equipped with a Mettler FP 80 central processor (Mettler, Columbus, OH), focused on a Leica DM LP microscope (E. Licht Co. , Denver, CO). The effects of the temperature increase on the behavior as crystals of the samples were studied by placing a small amount of each sample on a glass slide, covering it with a coverslip, and gradually increase the temperature to approximately 300 ° C at a heating rate of 10 ° C / minute. Dehydration was observed with the samples submerged in mineral oil. The photographs were taken using a Nikon 100 Nic digital camera equipped with a Diagnostics Instruments 1X-HRD digital camera coupler (Diagnostics Instruments Inc., Sterling Heights, MI) and transferred to a computer. X-ray powder diffraction (PXRD) The PXRD standards of different carbendazim salts were determined at room temperature and atmospheric pressure using a Philips PM 990/100 diffractometer (Philips, The Netherlands). The x-ray generator (P 3373/00 Cu LFF DK119706) has a copper radiation source that generates a voltage of 50 kV and a current of 40 mA. The counts were measured using an X'Celerator detector, which is based on the technology of multiple strips in real time (RTMS, for its acronym in English). The samples were packed in zero-depth silicon sample holders and precautions were used to avoid introducing the preferred orientation of the crystallites. The samples were subjected to a turning movement that had a rotation time of 4 s. The samples were explored with the diffraction angle, 2T, increasing from 3o to 63 °, with a progressive step of 0.0167 ° and a counting time of 15.24 s. The Traces of the XRD pattern of the samples (salts subject to moisture sorption or stability) were compared with respect to the position of the ridge and the relative intensity, change of ridge and the presence or absence of ridges in certain angular regions. Moisture sorption studies The moisture sorption of the various salts was determined by exposing weighted amounts (~ 2 to 3 mg) of salts in a 4 ml glass flask, which was placed in sealed desiccators containing saline, saturated solutions . Saturated, saturated solutions that provide relative, defined humidities (as a function of temperature) have been reported in various manuals they contain. physical and chemical data. The current study was conducted at 25 ° C with relative humidity values of 43% (saturated potassium carbonate solution) and 81% (saturated solution of potassium bromide). The samples were stored in relative humidity desiccators, known for 8 days, after which they were weighted again to calculate the% change in weight. The solid phases were then analyzed using a PXRD to assess the effect of moisture content. Determination of solubility An amount of each crystalline carbendazim salt that exceeded the amount required to produce a solution saturated with respect to the salt (unless the solubility exceeded 1 M) was rotated for 4 to 7 days in a 4 ml glass vial containing 1-2 ml of Millipore ™ water at room temperature. The solubility of the salts in water at 37 ° C and 45 ° C was determined by placing the flasks in constant temperature, calibrated water baths (Jouan Inc., Winchester, VA) maintained within 0.05 ° C of the temperature of the run. These were mixed by end-to-end rotation. Each sample was then filtered through a 0.45 μp PVDF filter? . The filtrate was collected in two or more fractions, which were analyzed separately by the HPLC to ensure that there were no misleading solubility measurements resulting from the adsorption in the filter. It was assumed that the adsorption on the filter was insignificant when the concentration of the successive fractions was within ± 5%. The composition of the residual solid was examined to ensure that at least some of the solid phase that was in equilibrium with the solution was actually salt. The solubility of the different salts was also determined at 0.01 and 0.1M of the corresponding acids. Generally, determinations of the Ksp value were calculated directly from the observed concentration of carbendazim once it was established that the solid phase, residual contained an excess of salt. Since the precipitation of free acid results in the neutralization of an equivalent amount of counterion to its free base form, the same procedure could be used to calculate the Ksp value in the systems where free acid precipitation occurred prior to saturation of the free acid. system with the given salt. Dissolution studies The solution of carbendazim and its salts at room temperature was studied in Millipore ™ water and 0.1N hydrochloric acid (HC1) at pH 1.09. The dissolution of physical mixtures of drug and phosphoric acid in the molar ratios of 1: 1 and 1: 2 was also studied. A weighted amount of salt (in order to have 50 mg of carbendazim) was ground to provide a uniform particle size and suspended in dissolution media. The volume of the dissolution media was 250 ml and the stirring speed was maintained at 250 rpm. Samples of aliquots of a mi filtered through a MilliporeMR filter 0.45 μt? they were removed in 1, 5, 10, 15, 20, 30, 45 and 60 minutes, respectively. A mi of the dissolution medium was added to the dissolution vessel after each sampling period to maintain a constant volume. The samples were then analyzed by HPLC.

High Resolution Liquid Chromatography A CLAR Beckman Gold system equipped with a model detector no. 168 to 280 nm was used for all the assays. A Pinnacle ODS amine column (250 x 4.6 mm, Restek, Bellefonte,) was used with a mobile phase composed of 40 mM phosphate buffer at 40% at pH 3 and 60% acetonitrile. The flow rate was controlled at 0.8 ml / minute, with a carbendazim retention time of 3.5 minutes. The injection volume was 20 L. The evaluation of the assay was conducted by the use of standard solutions of carbendazim in concentrations ranging from 0.1 μg / ml to 100 μg / ml. None of the solubilization agents interfered with the assay. All the experimental data are the average of values in duplicate with an average error of less than 3%. X-ray Structural Analysis of a Crystal, Individual A colorless block of carbendazim phosphate having approximate dimensions of 0.07 x 0.22 x 0.37 was mounted on a glass fiber in a random orientation. Examination of the glass on an X-ray diffractometer of the Bruker SMART 1000 CCD detector at 443 (2) K and a power setting of 50KV, 40tnA showed a measurable diffraction at least T = 24.4565 °. The data were collected in an S ART1000 system using monochrome graphite Mo K radiation (= 0.71073Á).

The initial cell constants and an orientation matrix for integration were determined from reflections obtained at three orthogonal angles of 5o of reciprocal space. A total of X frames were collected in 1 detector setting that covered 0 < 2T < 60 degrees, which had a scanning width? of 0.3 and an exposure time of 10 seconds. The frames were integrated using the narrow-frame algorithm of the Bruker SAINT computer program package. Of the 7239 total reflections that were integrated and retained, 2676 were unique (redundancy = 2.7, Rint = 2.8%, Rsig = 3.2%). Of the unique reflections, 2287 (85.5%) were observed with 1 > 2s (1). The triclinical, final cell parameters of a = 7.7610 (9) A, b = 9.0368 (11) A, c 9.9799 (11) A, a = 115.098 (2), ß = 104.913 (2),? = 98,536 (2), volume = 585.36 (12) Á3 are based on refining the XYZ centroids of 3034 reflections with 1 > 3s (1), which cover in a range of 2.4125 < T < 24.4565. Empirical absorption and decline corrections were applied using the SADABS program. The absorption coefficient is 0.265 mm "1, Tmin = 0.9084 and Tmax = 0.9817. For Z = 2 and the weight of the formula (FW) = 289.19, the density calculated is 1641 g / cm3. systematic absences and intensity statistics indicate that the space group was P 1 (# 2), which was consistent with refining.

The structure was solved using SHELXS in the Bruker SHELXTL software package (Version 5.0). The refinements were made using SHELXL and the illustrations were made using XP. The solution was achieved using direct methods followed by Fourier synthesis. The hydrogen atoms were added in idealized positions, restricted to travel on the atom to which they are attached and which have thermal parameters equal to 1.2 or 1.5 times UISO ¿that atom attached. The minimum quadratic refinement of the complete, anisotropic, final matrix based on F2 of all the reflections converged (maximum change / esd = 0.000) in Rx = 0.0421, wR2 = 0.0987 and goodness of fit = 1.060. The "conventional" refining indices that use the 2287 reflections with F > 4a (F) are Rx = 0.0349, wR2 = 0.0941. The model consisted of 220 variable parameters, 0 conditioning factors and 0 restrictions. There were 24 correlation coefficients between 0.555 and 0.633 due to the obtuse angle, which includes thermal parameters outside diagonal. The highest peak in the final difference map was 0.468 eA "3, located 0.66 of C (8) .The lowest peak occurred at -0.303 eA" 3, located 0.59 of P (l). The dispersion factors and the anomalous dispersion were taken from the international tables Volume C, tables 4.2.6.8 and 6.1.1.4.

The determination of the x-ray structure of a crystal for all of the other salts was carried out in a manner similar to that described above. The data are summarized in table 2. RESULTS AND DISCUSSION Morphology of Carbendazim Salts After the preparation and recovery of the crystalline forms, the visual and microscopic evaluation (figure 1) clearly showed differences in the morphology of the salts prepared to from the original compound. Using microscopy, all salt salts examined were characterized as either monocyclic or orthorhombic. X-ray Diffraction Analysis Each of the prepared salts had a characteristic, distinct PXRD pattern, as shown in Figure 2. These PXRD standards were compared with the respective samples that were subjected to moisture sorption studies or studies. of stability.

Table 2a. Crystallographic data for the X-ray structure of a crystal of different carbendazim salts Data of the Crystal Hydrochloride Phosphate Sulfate Cough and the Benzoylate Mesylate Empirical Formula C9H14CIN304 C18H24N6O10S Ci6H17 305S Ci5H15N305S C10H13N3O5S Weight of the formula 263.68 289.19 516.49 363.39 349.36 287.29 Crystal Size 0.55 x 0.12 x 0.37 x 0.22 x 0.25 x 0.12 x 0.34 x 0.09 x 0.39 x 0.35 x (mm3) 0.08 0.07 0.04 0.08 0.18 Monoclinic Truncal Orthorhombic Orthopedic Triclinic System Monoclinic Triclinic Crystal Space group P212121 ?? C2 / c P212121 P1 Ce a = 5.6916 (7) a = 7.7610 (9) a = 19.666 (4) a = 7.6805 (7) a = 9.0068 (5) a = 5.1602 (8) b = 13.3375 (17) b = 9.0368 (11) b = 6.7980 (15) b = 13.4035 (12) b = 9.3944 (5) b = 17.688 (3) Dimensions of the c = 15.4889 (19) c = 9.9799 (11) c = 18.250 (4) c = 15.9194 (14) c = 9.6643 (6) c = 14.321 (2) unit cell (A) cx = 90 ° a = 115.098 ° cc = 90 ° a = 90 ° a = 87.9450 ° a = 90 ° ß = 90 ° ß = 104.913 ° ß = 115.687 ° ß = 90 ° ß = 75.7680 ° ß = 98.150 °? = 90 ° 7 = 98.536 °? = 90 ° 7 = 90 ° 7 = 74.9240 ° 7 = 90 ° Volume (A3) 1175.8 (3) 585.36 (12) 2198.7 (8) 1638.8 (3) 765.01 (8) 1293.9 (3) Z 4 2 8 4 2 4 Calculated density 1,490 1,641 1,560 1,473 1,517 1,475 5 (mg / m3) Absorption Coefficient 0.333 0.265 0.218 0.231 0.244 0.271 (mirf1) F (000) 552 300 1080 760 364 600 10 Table 2b. Crystallographic data for the X-ray structure of a crystal of different carbendazim salts Collection of Hydrochloride Phosphate Sulphate Tosylate Benzoylate Mes i lato 5 data Bruker Diffractometer SMART Bruker SMART Bruker SMART Bruker SMART Bruker SMART SMART 1000 CCD 1000 CCD 1000 CCD 1000 CCD 1000 CCD 1000 CCD Temperature () 170 170 170 170 170 170 Wavelength 0.1707 0.7107 0.7107 0.7107 0.7107 0.7107 (A) Range of T for collection 2.01-26.11 ° 2.41-27.54 ° 2.30-27.52 ° 1.99-25.55 ° 2.18-27.90 ° 2.30-26.03 ° of data -7 < h < 7, -10 < h < 10, -25 < h < 25, -9 < h < 9, -11 < h < 11, -6 < h < 6, Index ranges -16 < k < 16, -11 < k < 11, -8 < k < 8, -16 < k < 16, -12 < k < 12, -21 < k < 21, -18 < l < 19 -12 < l < 12 -23 < I < 23 -19 < I < 19 -12 < I < 12 -17 < I < 17 Reflections 12994 7239 13030 17552 9724 7047 collected Reflections 2321 2676 2540 3062 3619 2569 independent Table 2c. Crystallographic data for the X-ray structure of a crystal of different carbendazim salts Solution and Hydrochloride Phosphate Sulfate Tosylate Benzoylate Mesylate Refining System used SHELXTL-V5.0 SHELXTL-V5.0 SHELXTL-V5.0 SHELXTL-V5.0 SHELXTL-V5.0 SHELXTL-V5.0 Solution Methods Methods Methods Methods Methods Direct direct direct direct direct direct methods Minimum Minimum Minimum Minimum Minimum Refining method quadratic quadratic quadratic refining quadratic quadratics of full-matrix quadratics complete matrix complete matrix complete matrix complete matrix complete matrix in F2 in F2 in F2 in F2 in F2 in F2 Transmission 0.9732 and 0.9817 and 0.9913 and 0.9817 and 0.9580 and Max / Min 0.8380 0.9084 0.9476 0.9255 0.9107 Parameter of the structure -0.03 (7) 0.01 (9) 0.32 (8) absolute Data / restrictions / 2321/0/170 2676/0/220 2540/0/195 3062/0/226 3619/0/217 2569/2/173 parameters Indices R Ri = 0.0397, Ri = 0.0349, Ri = 0.0419, = 0.0433, R, = 0.0369, R, = 0.0384, 5 (1 > 2s (1)) wR2 = 0.0714 wR2 = 0.0941 wR2 = 0.0954 wR2 = 0.0828 wR2 = 0.0899 wR2 = 0.0892 Indices R (all R-i = 0.0523, Ri = 0.0421, R = 0.0738, Ri = 0.0538, Ri = 0.0509, Ri = 0.0437, the data) wR2 = 0.0754 wR2 = 0.0987 wR2 = 0.1098 wR2 = 0.0860 wR2 = 0.0933 wR2 = 0.0915 Goodness of fit 1.073 1.060 1.041 1.084 0.977 1.062 in F2 10 Crest and difference cavity plus 0.301 and -0.188 0.468 and -0.303 0.290 and -0.380 0.318 and -0.256 0.366 and -0.364 0.286 and -0.224 large (eÁ "3) Thermal Analysis A summary of the DSC data is provided in Table 3, which includes all thermal events (ie dehydration and fusion) and their corresponding heat requirements. The DSC traces of each salt (figure 3), except hydrochloride and sulfate, showed an individual fusion endotherm, indicating that they were synthesized as anhydrous salts. On the other hand, traces of DSC sulfate and hydrochloride showed more than one endotherm, suggesting the presence of the solvent molecule and / or polymorphs. Since water was the only solvent used in each salt preparation, it is believed that the two previous salts were hydrates. Table 3. DSC data of different carbendazim salts with respect to thermal events at a certain temperature with the corresponding heat required.

Heat Endotherm Salt Melting point endotherm Heat of carbendazim dehydration (J / g) (° C) melting (° C) (J / g) Temperature Temperature Initial maximum Hydrochloride 66.52 124.8 96.75 118.76 219.4 Phosphate - 180.23 189.54 296.9 Sulfate - - 124.04 137.31 323.6 Mesylate - 198.48 202.45 137.8 Besilate - 208.17 211.23 171.0 Tosylate - 213.18 216.47 162.7 Hot stage microscopy (HSM) was used to discover the different thermal events that were shown in the DSC traces of the hydrochloride salt and the sulfate salt. Figure 4 shows the sequence of events recorded while heating a sample of carbendazim sulfate. With heating, the first endotherm (A) at 135 ° C in the DSC trace of the sulfate salt probably corresponds to the molten material of the salt accompanied by the dehydration of the hydrated salt. The formation of air bubbles indicates the release of water molecules and the contraction of the molecules represents the molten material. The basis of this endotherm was further investigated using the TGA. The TGA scan shown in Figure 5 indicates a weight loss of approximately 19% over the temperature range of 120-170 ° C. This weight loss is greater than the theoretical weight loss of 7%, calculated for a solvate consisting of two molecules of carbendazim, two water molecules and a single molecule of sulphate. Therefore, the first endotherm must represent the molten material of the hydrate. As the sample is further heated, a second form of the compound is recrystallized from the molten material; however, this event was not detected by the DSC analysis. The molten material of this form corresponds to the second smallest endotherm (B) in the DSC thermogram and occurs around 175 ° C. In order to verify the assumption with respect to the second salt form, the sulfate salt was heated in an oven maintained at 140 ° C, then the sample was conducted in the HPLC using the procedure previously described to monitor the presence of carbendazim . The eluent in 3.5 minutes had a UV radiation spectrum similar to the original compound, validating the assumption. After the second fusion, recrystallization occurs again to form dendritic crystals. This dendritic crystal continues to grow until it melts, as indicated by the third endotherm in the DSC trace, which becomes the degradation product. The temperature of the first endotherm exceeds the boiling point of water by 35 ° C, indicating the formation of a stable, ionic hydrate. This is confirmed by a detailed study of its order of compaction, where the presence of water molecules helps in the formation of a variety of hydrogen bonds. The host water molecules in the sulfate salt are located in isolated cavities along the length of the b axis, forming H bonds with sulfate, carbendazim and other water molecules. Therefore, dehydration of the crystal should include complete rupture of the crystal structure, as shown in Figure 6, and should occur at a relatively high temperature due to the strong binding of the host-host hydrogen and the location of the host molecules in the isolated cavities. The DSC thermogram of sulfate, together with TGA and the HSM confirmed that there were two forms of the sulfate salt. Although the synthesized salt contains only one form, it is only after the fusion of A that the other form grows from the molten material. From the DSC thermogram of the sulfate salt it is difficult to distinguish between monotropy and enantiotropy. The interpretation of the DSC curve is facilitated by the Burger enthalpy of the fusion rule: if the highest fusion form has a lower fusion enthalpy, both forms are enantiotropically related. Table 4 lists the melting point and melting enthalpy for the different sulfate forms and the hydrochloride salts. The melting enthalpy of the highest fusion form B is less than the fusion enthalpy of A. Therefore, the two forms are enantiotropically related, however only form A is stable below the transition temperature. In a similar manner, it was discovered that the hydrochloride salt is subjected to dehydration at 66 ° C, followed by the melting endotherm at 120 ° C. The weight loss of 13.1% (Figure 5) over the temperature range of 45-86 ° C agrees with the theoretical value of 13.6%, which was calculated for a solvate containing two water molecules for each molecule of salt of hydrochloride.

It was discovered that the hydrochloride salt has three forms, which are also enantiotropically related. Table 4. Physical properties of different forms of a sulfate and a hydrochloride salt The kinetics of dehydration of carbendazim hydrochloride dihydrate was studied by holding the crystals at the TGA heating rates of 5, 7, 10, 12 and 15 ° C per minute. The TGA traces of that analysis are shown in Figure 7. The activation energy (Ea) for the dehydration process was calculated from these TGA data according to the method described by Flynn and Wall (JH Flynn and LA Wall, J. Research Nat. Bur. Standards A, Phys. Chem. A71, 25 (1967), J. Polym, Sci., Pol. Lett., 5, 191 (1967), J. Polym, Sci., Pol. Lett., 4, 323 (1966)). This method involves the analysis of the weight loss against the temperature at different heating rates (ß) to determine the absolute temperatures, corresponding to a constant weight loss (C). The graphics of negative logarithm of heating rates (expressed in ° C / s) (-log ß) against l / T a diagram was placed (figure 8) and the calculated activation energy of the slope of the curves. The activation energy for the dehydration of the hydrochloride, calculated from the TGA data, was ~ 64 kJ / mol. Comparison of structures of different carbendazim salts The X-ray structure of the crystal of different carbendazim salts allowed a detailed analysis of the concomitant preferences, hydrogen bonding interactions and crystal compaction forces that probably determine the physical properties of these forms crystal clear The illustrations of these salts together with their atomic numbering are given in Figures 9 (a-f). Atomic, relevant, end positions, link lengths, link angles, torsion angles, thermal shifts, anisotropic positions, and hydrogen positions are not provided here. In the carbendazim molecule, there is a double bond between the C (3) and 0 (4) atoms (1,192 (3) Á), while C (3) and 0 (2) join individually (1,335 (3) Á ). The distance of the bond between C (3) and 0 (2) is less than that for a covalent, individual value of 1.41Á, which It suggests that atom 0 (2) has a partial characterization sp2, thus making the C (l) atom of the methyl group less flexible. The imidazole nitrogen atom N (14) is protonated, so that the C (6) -N (14) bond is elongated (1. 332 (3) Á). This proton is linked, via an intermolecular hydrogen bond, to the counterion, for example chloride ion Cl (17) (N (14) ... Cl (17) = 3.143 A) in the hydrochloride ion. Although it is possible that the proton (H (14)) has an intramolecular hydrogen bond with the 0 (4) oxygen atom of the carbamate group, the angle of the firm bond is far from linear (ZN (14) H (14Á) O (4) = 116.12). The positive charge of the carbendazim molecule is neutralized by the counterion of the acid portion, included. The cation formed is stabilized by resonance, with the positive charge fluctuating between the three nitrogen atoms N (5), N (7) and N (14). This is verified by the link lengths of C (6) -N (5) (1,346 (3) Á), C (6) -N (7) (1,338 (3) Á) and C (6) -N ( 14) (1332 (3) Á), which are between the link length values for an individual CN link (0.143 Á) and a double C = N link (0.127 Á). The above information regarding the structure of carbendazim is true for all salts formed. It was discovered that the portion of carbendazim in all the salts studied was ordered flat, regardless of the system of the crystal / space group and / or the counterion present in the crystal lattice. This is not surprising, since the presence of a benzimizal ring at one end makes the molecule a complete plane. Interestingly, the carbonyl group after the oxygen atom of the methoxy group imparts a slight sp2 character to the oxygen restricting thereby the free rotation of the methoxy group. This is confirmed by the inability of the oxygen atom to form a hydrogen bond with any available H donor. None of the salts demonstrated an intramolecular or intermolecular hydrogen bond between the carbendazim molecules, except for the sulfate salt, where there was a weak intermolecular hydrogen bond C-H ... O. Apart from the normal covalent bonds, the order of compaction of organic salts is determined mainly by their ability to form inter- and intramolecular hydrogen bonds and, to a lesser degree, by van der Waals interactions. In this way, the knowledge of the resistance of the hydrogen bonds together with the number of hydrogen bonds (HBN) can be used qualitatively for the correlations with the melting point. It should be remembered that a melting point of the compound is a function of several parameters, such as symmetry, eccentricity, compaction, flexibility and hydrogen bonding.

The resistance of a hydrogen bond is a function of the electronegativity of the donor atoms (D) and the receptor atoms (A). Since the proximity of the D and A atoms in a crystal is a measure of how effectively the hydrogen atom is acting as a mutual attractant, the crystallographic distances of A-B can be used as a measure of the hydrogen bond strength. HBN is defined as the maximum number of hydrogen bonds that can exist in a repeating network. It is equal to twice the minimum of any number of sticky hydrogen atoms or the number of hydrogen bonding sites in the molecule. Although all salts form multiple hydrogen bonds, only the prominent salts (based on resistance) are listed in Table 5. All the sulfonic salts form reinforced hydrogen bonds in which 3 NHs in carbendazim bind with 3 Os in sulfonate and, in this way, has relatively higher melting points than all the others. However, since the sulfonate salts are ordered by themselves to form hydrogen bonds, they will theoretically assume a compaction order that is less efficient than those of non-hydrogen bond molecules. This it is verified by the low values of compaction efficiency for the sulfonate salts. The phosphonate salt also forms reinforced hydrogen bonds between the phosphate moieties, however, the carbendazim molecule is only moderately bound to the phosphate and, therefore, has a lower melting point than the sulfonates, but higher than both the hydrochloride like sulfate. On the other hand, both the hydrochloride salt and the sulfate salt form a variety of H bonds (at least six), which can compete with each other and limit the formation of other bonds. It is very likely that the geometric constraints imposed by some H bonds can severely inhibit additional bonds, resulting in low melting points. Due to the less stringent requirements both the sulphate salts and the hydrochloride salts are packed tightly. Interestingly, the incorporation of solvent molecules in a crystal lattice seems to be positively or negatively related to achieving a maximum number of hydrogen bonds. The hydrochloride and sulfate salts are deficient in the receptor and donor atoms. The use of water as the solvent in these lattices is analogous to sharing electrons, allowing the hydrochloride and sulfate to achieve stable crystalline structures.

Table 5. Comparison of major hydrogen bonds formed in the crystal lattice of different carbendazim salts based on hydrogen bond resistance criteria Ad = [covalent (DH) + vdw (H ... 7A)] -discovered (DH ... A) it was discovered that the hydrochloride salt was dihydrate it was discovered that the sulfate salt was carbendazim emisulphate monohydrate aals of the molecule in the uni asymmetric c: volume of the unit cell calculated from the individual x-ray crystal data Carbendazim hydrochloride The carbendazim hydrochloride salt is crystallized in the orthorhombic space group P222i2i. This space group is chiral and has no symmetric operation associated with the inversion or mirror. In this way, it is exempt from a center of symmetry and is appropriately defined as a non-symmetric center. The symmetry operation for this spatial group includes both rotation and translation along a given axis, referred to as the helical axis. In this space group, three binary, helical axes are present along the directions a, b, and c. In this way, 2i2i2i means that the asymmetric unit moves ½ of a repeating unit along the three axes for every ½ of a revolution around that axis. Due to these symmetry operations, 4 equipuntual transformations are generated (x, y, z; ½ + x, ½-y, -z; -x, ½ + y, ½-z; 4-x, -y, ½ + z), thus having the multiplicity of general positions of 4 in the unit cell. The symmetric unit of the carbendazim hydrochloride salt contains one molecule each of hydrochloride and carbendazim, together with two water molecules. The presence of water molecules in the unit pattern illustrates the importance of water during the crystallization process.

The ellipsoidal, thermal diagram of the hydrochloride salt (Figure 9 (a)) includes the atomic labeling scheme, while the unit cell stereoscopic compaction diagram is shown in Figure 10. The chloride anion along with the molecules of Water act as a cross connector for the carbendazim assemblies. The self-assembly patterns of the carbendazim molecules (present as cationic species) are arranged by themselves in infinite helices around a binary, helical axis, which connects through the p-p stack that includes the imidazole and a phenyl ring ( Figure 10 (a)). These assemblies create cavities in which chloride ions and water molecules are contained (Figure 10 (b)). Chloride ions interact with the surrounding carbendazim ions and water molecules through multiple hydrogen bonds, a hydrogen bond with carbendazim (N (14) -H (14A) ... Cl (17)), and a hydrogen bond with each of the water molecules (0 (15) -H (15B). ..Cl (17) and 0 (16) -H (16A) ... Cl (17)). The water molecules also form hydrogen bonds with nitrogen (N (5) and N (7)) and oxygen (0 (4)) of the carbendazim ion. The two water molecules are also connected together through the intermolecular hydrogen bond. A novel feature in the assembly of carbendazim hydrochloride is the presence of the C-H ... C1 bond formed between Cl (H1A) of the methyl group in the carbendazim and the chloride ion. The distance of C (l) -H (1A). . .Cl (17) of 3.693Á is not only less than the van der Waals distance of 4.08Á but also maintains a remarkable linearity, the angle C-H. . . Cl is 157.82 °. The hydrogen bonding parameters for the hydrochloride salt are listed in Table 6. In the above-described compaction order of the hydrochloride salt, the Os atoms in the water act as receptors as well as hydrogen bond donors, while that both N and C act as hydrogen donors and Cl as a receptor. Table 6 Geometric parameters for hydrogen bonds observed in the crystal lattice of carbendazim hydrochloride salt DH ... A d (H ... A) (A) d (D ... A) (A) (DH ... A) (°) N (7) -H (7A) ... 0 (15) 1,786 2,664 174.79 N (5) -H (5A) ... 0 (16) 1,886 2,758 170.74 N (14) -H (14A) ... CI (17) 2,365 3,143 147.66 0 (15) -H (15B) ... CI (17) 2,297 3,070 160.82 0 (16) -H (16A) ... CI (17) 2,395 3,205 173.74 0 (15) -H (15A) ... CI (17) 2,456 3,249 151.04 0 (16) -H (16B) ... CI (16) 2,398 3,082 149.07 0 (16) -H (16B) ... C1 (15) 2,491 3,021 127.06 C (1) -H (1A) .. .CI (17) 2,767 3,693 157.82 D and A refer to donor and receptor atoms, respectively.

The structure of the crystal is stabilized by numerous hydrogen bonds of type N-H ... O, N-H ... C1, 0-H ... 0, 0-H ... C1 and C-H ... C1. Apart from these links, all other intermolecular contacts correspond to normal van der Waals interactions. Carbendazim Phosphate The carbendazim phosphate salt crystallizes in the triclinic system, which has a centrosymmetric space group, P. The triclinic crystal systems have no restrictions with respect to the edges of cells and cell angles. The only symmetry operation for space group P is the inversion through a point. Since this inversion is along a unit axis, it is equivalent to the center of symmetry. Based on this operation of symmetry, two equipuntual transformations (x, y, z and -x, -y, -z) can be obtained, which produces the multiplicity of general positions of 2 in the unit cell. The salt adopts a specific molecular conformation, which promotes intermolecular hydrogen bonding. Like the hydrochloride salt, this drug molecule is monoprotonated, with a molecular ratio of 1: 1 between the drug molecule and in phosphate anion. In this structure, the three N-H (N (4), N (7) and N (14)) donors of the drug molecule and the oxygen receptor of the phosphate anion participate in the hydrogen bond. Oxygen atoms 0 (12) and 0 (14) act as receptors and each form two H bond interactions, one with the protonated drug and the other with the phosphate anion. The atom 0 (13) acts as both a receptor (N (7) -H (10A) ... O (13)) and as a donor (0 (13) -H (13B). .0 (12)) to form H bond interactions. The O atom (11) acts as a donor, forming intermolecular H bonds with the 0 (14) atom of the phosphate anion. The N-H bond. . Intermolecular, strong between the NH atoms of the cationic drug moiety and the oxygen of the anionic phosphate serve to bind the neighboring carbendazim molecules in chains. Hydrogen bonds 0-H. . .0 between the phosphate molecules allow the ordering of anion molecules in a line parallel to e and b (Figure 11). Table 7 Geometric parameters for hydrogen bonds observed in the crystal lattice of the carbendazim phosphate salt DH ... A d (H ... A) (A) d (D ... A) (A) (DH ... A) (°) N (7) -H (10A) ... OR (13) 2,256 2,986 146.59 N (14) -H (13A) ... 0 (12) 1,946 2,695 150.58 N (5) -H (11A) ... 0 (14) 1,804 2,658 163.60 N (7) -H (10A) ... O (14) 2,599 3.110 121.02 0 (13) -H (13B) ... 0 (12) 1,804 2,583 177.66 0 (11) -H (11 B) ... 0 (14) 1,893 2,616 173.62 D and A refer to donor and receptor atoms, respectively.

The compaction rearrangement of the phosphate salt shows that both carbendazim and phosphate anions are arranged in parallel molecules stacks, while the molecules in adjacent stacks are ordered in inverted form. Inside the piles, all the molecules are ordered in the same direction. Apart from routine intermolecular hydrogen bonds (Table 7), the most intense intermolecular interactions in carbendazim occur between adjacent piles between the carbon atom of the carbonyl group and the p-system of the benzene ring. The observed link length (C (3) -C (10)) of 3.261Á is less than the van der Waals value of 3.4Á. The strong electron-withdrawing character of the carbonyl oxygen atom induces the formation of complexes d. Carbendazim sulfate Carbendazim sulfate is crystallized in the monoclinic system, which has a C2 / c centrosymmetric space group. In the monoclinic system, there is a "single" axis - which is perpendicular to the other two. This single axis is normally selected as the b-axis and, thus, β-90 °. The crystal pattern of the sulfate salt is centered, unlike the hydrochloride salt or the phosphate salt having primitive patterns. In a centered pattern, the grouping of configurations in the center of the rectangular cell is identical to that in the corners. The XC symbol indicates that the Reticle is centered on the face or centered on the vertex, with a second point of the reticle that is in the center of the face C (which is defined by the axes a and b). In these systems, the volume of cells is double that of the primitive cell. In C2 / c, the symmetry operation is a binary rotation axis parallel to the b axis and a sliding plane perpendicular to the b axis. The symbol Ac 'indicates that the sliding direction is parallel to the axis c. A. Sliding plane combines the operation of reflection with that of translation and, therefore, occurs only in extended orders. In this spatial group, 2 equipuntual transformations are generated by point symmetry, which is doubled (a 4) by centrosymmetry. Since this crystal system is one centered on the face, the number is further doubled to 8, thereby producing the multiplicity of general positions of 8 in the unit cell. This general positions are (x, y, z), (-x, -y, -z), (½ + x, ½ + y, z), (½-x, ½-y, -z), (- x, y, ½-z), (x, -y, ½ + z), (½-x, ½ + y, ½-z) and (½ + x, ½-y, ½ + z). In the smallest molecular unit, S042"sits on a binary axis such that only half of it is unique." The molecular relationship between the drug molecule and the anion is 2: 1. Therefore, the asymmetric unit It consists of a single protonated carbendazim molecule, a water molecule and a sulfate anion medium.

The sulfate salt adopts a molecular conformation that promotes intermolecular hydrogen bonding. In this structure, the three N-H donors of the drug molecule and the anion sulfate oxygen receptor, together with the water molecule, participate in the hydrogen bond. The intermolecular hydrogen bonds, strong between the groups of NHs (both imidazole and carbamate) and the oxygen atoms of sulfate or water are linked to the protonated carbendazim, the sulfate anions and the water molecules in chains, which are propagated to along the b axis (figure 12). Therefore, the compaction diagram of this salt closely resembles that of the phosphate salt, which has an anion column, S042"in this case, which runs parallel to the b axis, where the sulphate molecules are joined by hydrogen to the water molecules (0 (20) -H (21) ... 0 (10) and 0 (20) -H (20) ... O (ll)). The drug molecule is bound by H again to the anion on each side of the molecule, just as they do in the phosphate salt ((7) -H (7A) ... O (10), N (5) -H (5A) ... 0 (11), N (5) - H (5A) ... S (1) and N (7) -H (7A) ... S (1) .The drug molecule also forms hydrogen bonds with the molecule of water (N (14) -H (14A) ... 0 (20)).

Table 8. Geometric parameters for hydrogen bonds observed in the crystal lattice of the carbendazim sulfate salt DH ... A d (H ... A) (A) d (D ... A) (A) Z (DH ... A) (°) N (7) -H (7A) ... O (10) 1,839 2,689 165.86 N (5) -H (5A) ... 0 (11) 1,841 2,699 167.27 N (14) -H (14A) ... O (20) 2,031 2,800 147.82 N (15) - H (5A) ... S (1) 2,843 3,664 157.13 N (7) -H (7A) ... S (1) 2,858 3,639 150.36 O (20) -H (20) ... O (11) 2,082 2,900 160.92 OR (20) -H (21) ... O (10) 2,149 2,959 163.71 C (9) -H (9A) ... 0 (4) 2,500 3,411 150.09 D and A refer to donor and receptor atoms , respectively. The compaction order of the sulfate salt shows the presence of intermolecular hydrogen bonds that have carbon atoms as the hydrogen donor. The C (9) atom of the benzene ring also acts as a hydrogen donor, forming a hydrogen bond with the oxygen atom of the carbonyl group (C (9) ... 0 (4) = 3.411Á). Although it was understood as early as 1962 that an activated C-H group when present in some heterocyclic bases, for example, caffeine, theophylline, uric acid and related compounds, tends to interact with the oxygen atoms in the same way as a 0-H or NH group and the short C ... 0 contacts (< 3.4Á) observed in the crystals of these molecules were interpreted as hydrogen bonds CH ...OR. It was not until 1982 that the existence of hydrogen bonds C-H ... 0 in organic molecules was convincingly demonstrated and C-H ... 0 bonds began to gain acceptance as a stabilizing force when they were adjusted within the structure of major forces, such as hydrogen bonds N-H ... 0, 0-H ... 0 and donor acceptance interactions. Although the distance of C ... 0 for the C-H bond ... 0 in the sulphate salt is a little higher than the limit, the linearity of the bond angle (150.09 °) makes its existence more than possible. In addition, the order of compaction of the sulphate salt is stabilized by the presence of the C-H ... p interactions between the methyl group of a carbendazim molecule and the benzene ring of the other. These interactions are C (11) ... H (1C) (2.797Á) and C (10) ... H (1C) (2.676Á). Carbendazim mesylate Carbendazim mesylate salt, like sulfate, crystallizes in a monoclinic system, although the mesylate salt has a different spatial group. Ce. Also, a Unlike other carbendazim sulfonate salts, the Bravais reticulum for the mesylate salt is centered. The only symmetry operation associated with this spatial group is a sliding plane in the direction parallel to the c axis. This spatial group is chiral, which has a z value of 4. The general positions are provided by (x, y, z), (½ + x, ½-y, z), (x, -y, ½ + z) y (½ + x, ½ '-y, ½ + z). The asymmetric unit consists of one molecule each of protented carbendazim and anionic methane sulfonate. A projection along the axis b of the atomic ordering of the salt is represented in figure 13. The compaction consists of parallel, alternate stacks of carbendazim anions and protonated mesylate. These piles are parallel to the a axis (Figure 13), and within each pile, all the molecules are oriented in the same direction. These piles of carbendazim and methanesulfonic acid are held together by intermolecular hydrogen bonds and interactions of C -? ... p. All the NH groups in the carbendazim molecule act as hydrogen donors, while the O and S atoms in the mesylate anion behave as hydrogen receptors. Each anion of mesylate forms three bonds N-H ... 0, two bonds with the molecule of carbendazim on the right side and one with the other molecule of carbendazim in the left side (figure 13). The N (5) atom of carbendazim can also form an H bond with the S (18) atom of the mesylate anion, although the N (5) -H (5A) ... 0 (17) bond is more linear than N (5) -H (5A) ... S (18). The hydrogen bonding parameters are listed in Table 9. Apart from the H bonds, which are the interactions of individual, strong points with a very well defined geometry, there are other less defined, weaker interactions that are also responsible to keep the molecule together. An interaction of this type is C-H ... p, where a polarized C-H group interacts with the aromatic ring. The presence of an avid electron sulfonate group polarizes the methyl group of the mesylate, making it insufficient in electrons, which then interacts with the benzene ring with high electron content of carbendazim by forming C -? ... p interactions. The distance of 2.759Á between C (10) -H (19C) is smaller than the sum of its radii van der aal (2.9Á), which proves the presence of these interactions. Therefore, hydrogen bonds and van der Waals contacts give rise to a three-dimensional construction of the structure and increase stability.

Table 9 Geometric parameters for hydrogen bonding observed in the crystal reticulum of the carbendazim mesylate salt DH ... A d (H ... A) (A) d (D ... A) (A) Z (DH ... A) C) N (7) -H (7A) ... 0 (15) 1,827 2,696 168.80 N (14) -H (14A) ... 0 (16) 1,934 2,745 152.59 N (5) -H (5A) ... 0 (17) 1,850 2,730 178.77 N (5) -H (5A) ... S (18) 2,901 3,713 154.10 D and A refer to donor and receptor atoms, respectively. Carbendazim Besilate The carbendazim besylate salt, like the phosphate salt, crystallizes in the triclinic system and has a spatial group P, with Z = 2. The asymmetric bond consists of one molecule each of carbendazim and benzenesulfonic acid . Carbendazim appears as a flat molecule in the asymmetric unit, with benzenesulfonic acid perpendicular to it. The order of compaction of the salt shows the presence of the intermolecular hydrogen bond between the protented carbendazim anion and the benzene sulfonium anion (Figure 14). However, the intramolecular hydrogen bond or the intermolecular hydrogen bond between the two carbendazim molecules or the two benzenesulfonic acid molecules is not observed. As with the other salts, all the donor atoms of hydrogen (M) form hydrogen bonds with the hydrogen receptor atoms (0 and S). Unlike the hydrochloride and sulfate salts, however, the compaction configuration of the besylate salt allows the formation of two intermolecular hydrogen bonds including carbon as the donor. The carbon atoms of phenyl (C (22) and C (23)) of the benzenesulfonate anion form hydrogen bonds with the methoxy oxygen atom (0 (2)) of the carbendazim molecule. The link lengths (C ... 0) for both C-H ... 0 links are less than 3.4A, and the link angle is greater than 130 °. Due to the intermolecular hydrogen bonds between the carbendazim anion and the benzenesulfonate anion, the carbendazim molecules are arranged along the b-axis. Table 10. Geometric parameters for hydrogen bonds observed in the crystal lattice of the carbendazim besylate salt DH ... A d (H ... A) (A) d (D ... A) (A) Z (DH ... A) (°) N (7) -H (7A) ... 0 (7) 1,916 2,789 171.48 N (5) -H (5A) ... 0 (16) 1,908 2,772 166.76 N (14) -H (14A) ... 0 (15) 2,011 2,797 148.10 N (7) - H (7A) ... S (18) 2,894 3,686 150.67 C (22) -H (22A) ... 0 (2) 2,574 3,302 133.68 C (23) -H (23A) ... 0 (2) 2,588 3,334 135.67 D and A refer to donor and receptor atoms, respectively.

From the order of compaction of the besylate salt, it is clear that the carbendazim molecules stacks are arranged perpendicular to the benzene sulphonate anion stacks. This arrangement is favorable for having an electrostatic interaction of edge to face in the form of T. Although benzene does not have a net dipole, it has an irregular charge distribution, with higher electron density in the face of the ring, and an electron density reduced on the edge, thus giving rise to tetrapolo moments. It is thought that these tetrapolo moments of the aromatic rings are the precursors for the electrostatic component of the interaction. The possible side-to-side interactions observed in the besylate salt are H (9A) ... C (23) and H (9A) ... C (22), which have link lengths of 2,696Á and 2,736Á , respectively. Carbendazim tosylate The carbendazim tosylate salt crystallizes in the orthorhombic system of the space group P21212i, which is chiral. This spatial group has no symmetry operation associated with the inversion or mirror and, thus, is devoid of a center of symmetry and is appropriately defined as without a symmetric center. The symmetry operation for this spatial group includes both rotation and translation along an axis helical. In this space group, three binary, helical axes are present along the directions a, b, and c. In this way, 2 2 2 means that the asymmetric unit moves ½ of a repeating unit along the three axes for every ½ of a revolution around that axis. Due to these symmetry operations, 4 equipuntual transformations are generated (x, y, z; ½ + x, ½-y, -z; -x, ½ + y, ½-z; ½-x, -y, ½ + z), thus having a multiplicity of general positions of 4 in the unit cell. The asymmetric unit consists of one molecule each of carbendazim and toluenesulfonic acid. As seen in Figure 9 (f), the carbendazim molecule and the toluenesulfonic acid are perpendicular to each other. The unit cell contains four molecules each of carbendazim and toluenesulfonic acid. The molecules are arranged in alternating layers of carbendazim and tosylate, in all three directions (Figure 15). The carbendazim and tosylate molecules in the tosylate salt are arranged in infinite helices around a binary, helical axis. When the crystallographic c-axis is called, the carbendazim molecules inside the piles are loosened by 180 °, while the tosylate molecules are oriented in the same direction. In this case, the molecules of adjacent carbendazim stacks show an angle of inclination of: + 41.11 ° to the axis of the stack, which is the axis a of the case.

As expected, the tosylate compaction order (Figure 15) shows an intermolecular hydrogen bond (Table 11) between the NH groups of carbendazim and the 0 and S atoms of tosylate. The order of compaction for tosylate, such as besylate, shows a number of edge-to-face interactions as well as CH-p. These interactions are not only between the phenyl rings of carbendazim and p-toluenesulfonic acid but also between the methyl group of carbendazim and the phenyl ring of p-toluenesulfonic acid. Some of the interactions observed are H (9A) ... C (23) (2.769Á), H (9A) ... C (2) (2.786Á) and H (1A) ... C (23) ( 2.779Á). Taba 11. Geometric parameters for hydrogen bonds observed in the crystal lattice of the carbendazim tosylate salt DH ... A d (H ... A) (A) d (D ... A) (A) Z (DH ... A) (°) N (7) -H (7A) ... 0 (15) 1,845 2.713 167.93 N (5) -H (5A) ... 0 (16) 1.912 2.786 171.85 N ( 14) -H (14A) ... 0 (17) 2,075 2,812 140.74 N (7) -H (7A) ... S (18) 2,871 3,665 150.89 N (5) -H (5A) ... S ( 18) 2,979 3,798 151.79 C (25) -H (25B) ... 0 (2) 2,582 3,442 146.60 D and A refer to donor and receptor atoms, respectively.

Efficiency of Compaction The forces of compaction and the symmetry of the crystal determine the chemical and physical properties of crystalline materials. The primary compaction rule for molecular crystals, called the Kitraigorodskii Narrow Compact Principle, is to maximize density and minimize free volume. Although the empty space between the crystals is undesirable, it is usually unavoidable. As long as the glass is denser or packed more tightly, the lower the free energy, resulting in greater stability. The compaction efficiency can be interpreted by measuring the compaction coefficient,?, For a given crystal. The compaction coefficient represents the amount of space filled by the molecules in a lattice and is calculated as Vceldilla where N the number of molecules in the unit cell, Vdw is the van der Waals volume of the molecule in the asymmetric unit and Vceidiiia is the volume of the unit cell. The van der Waals volumes represented were calculated using the Conolly surface feature of the DS ViewerPro program and the standard van der Waals radios included in the computer program. The compaction coefficients of various carbendazim salts are listed in Table 12. The compaction coefficients for all the salts are between 0.65 and 0.73, which is consistent with the é range of 0.65-0.8 for stable crystals. Table 12. Compaction Coefficients of Sales of Carbendazim Moisture sorption studies A high degree of sorption or desorpción of humidity by the salts to 30-50% of RH, the humidity conditions expected of the pharmaceutical manufacturing plants can create numerous difficulties of manipulation and manufacture that include the change in the potency and the actual density of the drug, variation in flow properties, dissolution rates and bioavailability, as well as chemical instability. Although general tendencies have been observed between the propensities of salts to form hydrates and various structural characteristics, such as radii and charge of counterions, a given salt can form several stoichiometric hydrates depending on the crystallization conditions. Therefore, a valuation The ability of a compound to adsorb moisture is an important developmental criterion. Figure 16 shows the moisture adsorption curves for the carbendazim salts under relative humidity values of 43 and 81%. As can be seen, the hydrochloride and sulfate salts were minimally hygroscopic, adsorbing less than 1% moisture at both 43 and 81% RH. Incidentally, both salts were synthesized as hydrates. In contrast, it was discovered that phosphate and mesylate salts were highly hygroscopic, adsorbing 7.5 and 10.1% humidity at 81% RH compared to 1-2% at 43% RH. The besylate and tosylate salts adsorbed less than 1% moisture at 43% RH and about 4.3% at 81% RH. The powder x-ray diffraction patterns of the hydrochloride, sulfate, besylate and tosylate salts remained unchanged for moisture values of 43 and 81%. However, both mesylate and phosphate salts showed changes in their PXRD patterns for samples stored at 81% RH, which could be attributed to a change in crystal shape (Figure 17 (a) and (b) ). The sample of mesylate stored at 81% RH loses intensity at higher angle crests as well as reflections greater than 11.7 ° 2? and 20.3 ° 2 ?, and gains a new peak at 18.8 ° 2T, while the sample stored at 43% RH It has a similar PXR pattern as the synthesized salt. The phosphate sample stored at 43% RH loses intensity at a reflection of 28 ° 2 ?, while the 81% RH pattern has a new reflection at 26 ° 2 ?, and loses intensity at 22 ° 2T. These results indicate that at a RH value of 43%, all salts adsorbed less than 2% moisture from the atmosphere. Although this caused the phosphate salt to change shape, the other salts remained unchanged in their solid state form. Solubility studies The aqueous solubilities of the carbendazim hydrochloride, phosphate, sulfate, besylate and tosylate salts at 25 ° C are listed in Table 13. It was found that the mesylate salt is highly soluble (> 200 mg / ml) and, therefore, its saturable solubility was not determined. The sulphate solubility reached a plateau at approximately 1.2 x 10"2 in the lower region at pH 1.58, indicating that the solution is saturated with respect to the sulfate salt below this pH. mesylate as well as tosylate decreased below a pH value of 1.65 and 1.82, respectively The solubility products of the different salts are also shown in table 13.

Table 13. Solubility of different carbendazim salts a - Saturation was not reached. b - Ksp value calculated after correcting the common ionic effect. The solubility dependencies at the temperature of the different salts were also studied. This is a semilogarithmic diagram of the solubility against the reciprocal temperature. The slopes of these diagrams (or the tangent for a curve given at a given temperature, in the case of a non-linear diagram) produce the differential heat of solutions of the respective species. Usually, these curves are not linear and the values ?? 3 are obtained calorimetrically at a given temperature.

Within the limited temperature range of this investigation, the diagrams appear linear and approximate estimates of the values are possible. Table 13 lists the values ?? 3 for all the compounds studied. Dissolution studies The dissolution behavior of the free base, as well as the hydrochloride, phosphate, sulfate, mesylate, besylate and tosylate salts were compared in Millipore ™ water and 0.1 N hydrochloric acid solution at pH 1.1. The solution at pH 1.1 simulates the gastric fluid (pH 1-3 in the stomach), since the behavior of this solution is relevant to bioavailability after oral administration. Figures 18a and 18b show the dissolution profiles in water and 0.1N HC1. As seen in Figure 18 (a), the hydrochloride, sulfate, besylate, tosylate and phosphate salts as well as the free base form did not completely dissolve in water. Each of these five salts dissolved more than 40% of the initial dose after 60 minutes. At the ends, the free base dissolved less than 1% after 60 minutes, while the mesylate salt was completely soluble in water within only 30 minutes. minutes The dissolution of each salt in 0.1N HC1 is shown in Figure 18 (b). The six salts and the free base were completely soluble in these dissolution media. The time for 100% dissolution of the sample crystals was different. The mesylate salt was instantly soluble, while the sulfate salt and the phosphate salt took 5-10 minutes to achieve complete miscibility. The free base together with the hydrochloride, besylate and tosylate were completely dissolved in 15-20 minutes. In order to compare the dissolution of the prepared salts with the physical mixtures of the free base and the acid, mixtures of carbendazim: phosphoric acid were prepared in the molar ratios of 1: 1 and 1: 2. Figure 19 shows the dissolution profile of the two physical samples and the phosphate salt in Millipore1"1 water.The phosphate salt (which was found to be 1: 1) shows better dissolution than the physical mixture of 1: 1. On the other hand, the physical mixture of 1: 2 shows better dissolution than the phosphate salt Due to the excessive acid, it is believed that the physical mixture of 1: 2 decreases the pH of the diffusion layer in the microenvironment of the particles more that salt phosphate 1: 1, facilitating the dissolution. A salt exhibits a dissolution rate higher than the base at any given pH, despite having the same equilibrium solubilities. It is believed that the salt effectively acts as its own "buffer" to alter the pH of the diffusion boundary layer, thereby increasing the apparent solubility of the precursor drug within that layer. In this way, the administration of basic drugs in their salt forms ensures that the stomach void, preferably that dissolution in vivo, will be the limiting factor of the speed in its adsorption. From the dissolution studies, it is evident that the salts formed have better dissolution than the free base. In water, the mesylate dissolves faster. In 0.1N hydrochloric acid, the given amount of the six salts (equivalent to 50 mg of carbendanzim) as well as the free base (50 mg) was completely dissolved within 20 minutes. The phosphate salt (1: 1) had better dissolution than the physical mixture of 1: 1 carbendazim and phosphoric acid, while the physical mixture of 1: 2 had the greater dissolution of the three due to the excessive amount of phosphoric acid .

A variety of acid salts of the amphoteric electrolyte, weak carbendazim were synthesized in order to increase the apparent solubility. A previous formulation study was conducted on all the synthesized salts. Table 14 lists the physical properties of the salts studied together with the free base. All salts showed better dissolution velocity profiles than the free base, with the mesylate having the best dissolution time. The hydrochloride and sulfate salts were synthesized as hydrates and found to exist in more than one form.

Table 14. Comparison of some basic properties of carbendazim and six salts Property Base Hydrochloride Phosphate Sulphate Mesylate Besylate Tosylate Appearance Light Gray, White, White, White, White, White, White, Crystal clear crystalline crystalline crystal clear crystal NA Crystal System Orthorhombic Triclinic Monoclinic Monoclinic Triclinic Orthorhombic Space group NA P2i2A P 1 C2 / c Ce ?? 2? 2? Weight Mol. 191.2 263.68 289.2 516.49 287.29 363.39 349.36 P.F. (° C) 240 118.76 189.54 137.31 202.45 211.23 216.47 Anhydrous hydrate anhydrous dihydrate anhydrous anhydrous anhydrous monohydrate Polymorphism No evidence At least three No evidence At least two No evidence No evidence No evidence of polymorphs forms of polymorphs forms of polymorphs of detected polymorphs of detected polymorphs Sw (mg / ml) 0.006 6,080 3,032 6,505 > 205,662 * 6,992 4,815 Solution pH 5.90 1.68 1.93 1.90 0.80 1.76 1.93 saturated theo% (min) pH 1 5 2-3 2-3 2-3 1 2-3 2-3 . (min) water NA ~ 5 ~ 5 ~ 3 < 1 ~ 5 ~ 5 Hygroscopicity Gain Gain Gain Gain Gain Gain Gain (Humidista during 0.36% from 0.13% from 0.88% from 0.38% of 2.04% from 0.18% from 0.27% of 8 days at 43% humidity humidity humidity, humidity humidity humidity humidity HR) pattern of same pattern PXRD of PXRD changed unsaturated solution with mesylate salt t¾o% and t6o% represents the time for dissolution of 40% and 60% of a given amount of salt / free base (equivalent to 50 mg of carbendazim ) Acid Formulations The free acid in the formulations comprising salts of the weak base compounds described in this text results in an improved dissolution of the free base compound. For example, the solution may be faster or more complete than in formulations that do not contain additional acid. The salt ratio of the free base to the free acid can be any ratio, however the ratios of about 1:05 to about 1: 3 are particularly useful, including all values and intermediate ratios therein. Particular examples of compositions include a phosphoric acid salt of a weak base combined with the free acid, phosphoric acid, in the relationships described above. Other particular examples of compositions of the invention include a hydrochloride salt of a weak base combined with a free acid, hydrochloric acid, in the ratios described above. Other particular examples of compositions of the invention include a sulfate salt of a weak base combined with a free acid, sulfuric acid, in the ratios described above. Other particular examples of compositions of the invention include a mesylate salt of a weak base combined with a free acid, methanesulfonic acid, in the ratios described above. Other examples Particular compositions of the invention include a besylate salt of a weak base combined with a free acid, benzenesulfonic acid, in the ratios described above. Other particular examples of compositions of the invention include a tosylate salt of a weak base combined with a free acid, toluene sulfonic acid, in the ratios described above. The free acid can be the same as the acid used to prepare the salt or it can be different. The free acid may also be a mixture of the acid used to prepare the salt and one or more acids not used to prepare the salt. A weak, particular base that is useful in formulations is carbendazim. In order to evaluate the importance of the free acid in the formulations, the dissolution profiles of the carbendazim tosylate salt and an equimolar physical mixture of carbendazim tosylate salt-p-toluenesulfonic acid were compared. The dissolution study was done in Millipore ™ treated water. A weighted quantity of salt or physical mixture (which has an equivalent of 50 mg of free carbendazim) was ground to have a uniform particle size and suspended in 250 ml of Millipore treated water. "11 Agitation rate was maintained at 250 rpm and the study was carried out at room temperature The samples of 1 ml aliquots filtered through a MilliporeMR 0.45 μp filter were removed in 1, 5, 10, 15, 20, 30, 45 and 60 minutes, respectively. 1 ml of the dissolution media was added to the dissolution vessel after each sampling period to maintain a constant volume. The samples were analyzed by a CLAR procedure. The dissolution of the carbendazim tosylate salt and the physical mixture of p-toluenesulfonic carbendazimide tosylate salt is shown in Figure 20. It is clear that the physical mixture shows better dissolution than the salt alone. Although the description is this text contains many specificities, these should not be considered as limiting the scope of the invention, but only provide illustrations of some embodiments of the invention. For example, salts of weak bases different from those specifically described in this text can be made using the description provided in this text. All references cited in this text are incorporated by this act as a reference to the degree consistent with the present description. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (21)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A pharmaceutical composition, characterized in that it comprises a salt of a weak base compound of the formula: wherein X is hydrogen, halogen, alkyl with less than 7 carbon atoms or alkoxy with less than 7 carbon atoms; n is an integer, positive less than 4; And it is hydrogen, chlorine, nitro, methyl, ethyl or oxychlor; is hydrogen, alkylaminocarbonyl, wherein the alkyl group has from 3 to 6 carbon atoms or an alkyl group having from 1 to 8 carbon atoms, and R2 is 4-thiazolyl, NHCOORi, wherein Ri is an aliphatic hydrocarbon with less than 7 carbon atoms or an alkyl group with less than 7 carbon atoms; one or more free acids; and optional pharmaceutical additives, wherein the salt and one or more free acids are present in the composition in a ratio of 1: 0.5 to 1: 3 by weight.
2. 2. The pharmaceutical composition according to claim 1, characterized in that the salt is one or more selected from the group consisting of: chlorides, bromides, phosphates, sulfates, tosylates, benzoylates, nitrates, sulfonates, formates, tartrates, maleates, maleates, citrates , benzoates, salicylates, ascorbates and mesylates.
3. 3. The pharmaceutical composition according to claim 2, characterized in that the salt is one or more selected from the group consisting of: chlorides, phosphates, sulfates, tosylates, benzoylates and mesylates.
4. 4. The pharmaceutical composition according to claim 1, characterized in that the salt and the free acid are present in the composition in a weight ratio of 1: 1.
5. 5. The pharmaceutical composition according to claim 1, characterized in that the salt and free acid are present in the composition in a weight ratio of 1: 2.
6. 6. The pharmaceutical composition according to claim 1, characterized in that the salt is crystalline.
7. 7. The pharmaceutical composition according to claim 1, characterized in that the pH of an aqueous solution or suspension of the composition is 2 or less.
8. 8. The pharmaceutical composition according to claim 1, characterized in that the weak base compound is an imidazole derivative.
9. 9. The pharmaceutical composition in accordance with Claim 8, characterized in that the weak base compound is where n is an integer from 1 to 3, R is hydrogen, alkyl having 1 to 7 carbon atoms, chlorine, bromine, fluoro, oxychlor, hydroxy, sulfhydryl or alkoxy having the formula -0 (CH2) and ( CH3), where y is an integer from 0 to 6.
10. 10. The pharmaceutical composition according to claim 1, characterized in that the weak base compound is a benzimidazole derivative.
11. 11. The pharmaceutical composition according to claim 10, characterized in that the weak base compound is carbendazim.
12. 12. The pharmaceutical composition according to claim 1, characterized in that the weak base compound is a pyridine derivative.
13. 13. The pharmaceutical composition according to claim 1, characterized in that the weak base compound is an aniline derivative.
14. 14. The pharmaceutical composition according to claim 1, characterized in that the composition is used for oral, intravenous or oral administration. infusion.
15. 15. The pharmaceutical composition according to claim 1, characterized in that the free acid has the same anion as the salt.
16. 16. The pharmaceutical composition according to claim 15, characterized in that it also comprises a free acid having a different anion than the salt.
17. 17. The pharmaceutical composition according to claim 1, characterized in that the free acid has a different anion than the salt.
18. 18. A solution or suspension, characterized in that it is of the pharmaceutical composition according to claim 1.
19. 19. A crystalline salt of a weak base compound of the formula: characterized in that X is hydrogen, halogen, alkyl with less than 7 carbon atoms or alkoxy with less than 7 carbon atoms; n is an integer, positive less than 4; And it is hydrogen, chlorine, nitro, methyl, ethyl or oxychlor; R is hydrogen, alkylaminocarbonyl, wherein the alkyl group it has from 3 to 6 carbon atoms or an alkyl group having from 1 to 8 carbon atoms, and R2 is 4-thiazolyl, NHCOORa, wherein ¾. is an aliphatic hydrocarbon with less than 7 carbon atoms or an alkyl group with less than 7 carbon atoms; wherein the salt is selected from the group consisting of: hydrochloride, phosphate, sulfate, tosylate, benzoylate and mesylate.
20. 20. The crystalline salt according to claim 19, characterized in that it also comprises one or more free acids.
21. 21. Use of a pharmaceutical composition according to claim 1 for treating a disease.