DESC:Technical field of Invention:
The present invention relates to new solid forms of the anti-mycotic drug Clotrimazole (CLT) with pharmaceutically acceptable coformers, such as 2,5-Dihydroxybenzoic acid (2,5DHBA), 2,4,6-Trihydroxybenzoic acid (2,4,6THBA), p-Coumaric acid (PCA), Caffeic acid (CFA), Adipic acid (ADA), Maleic acid (MA), Suberic acid (SBA), 2,4-Dihydroxybenzoic acid (24DHBA) , 2,6-Dihydroxybenzoic acid (26DHBA), 3,4-Dihydroxybenzoic acid (34DHBA) , 3,5-Dihydroxybenzoic acid (35DHBA) with exhibit improved solubility and dissolution rate, and to its process for preparation thereof.

Background of the Invention:
Clotrimazole 1-[(2-chlorophenyl)diphenylmethyl]-1H-imidazole an imidazole derivative used as antifungal powder. The drug can also works against different strains of Plasmodium Falciparum (Saliba, K. J.; Kirk, K. Trans. R. Soc. Trop. Med. Hyg. 1998, 92, 666–667). Malaria has become a global peril due to the spread of resistance to quinolone based antimalarial drugs such as quinine, chloroquine and mefloquine. The World Health Organization (WHO) has recommended artemisinin combination therapy (ACT) as a first line treatment for uncomplicated malaria instead of artemisinin based monotherapies (World Malaria Report 2010). Pharmaceutical companies are generally averse to registering drug products for tropical parasitic diseases including malaria due to increased cost of development and inadequate commercial returns. Efforts to develop new drugs through “repurposing” and “piggy back” approach (Gelb, M. H. Curr. Opin. Chem. Biol. 2007, 11, 440–445) are new ways to reduce cost of drugs targeting multidrug resistant plasmodium species.
According to the Biopharmaceutical Classification System (BCS), clotrimazole is a class II drug of poor aqueous solubility (0.49 µg/mL) and high permeability (log P 6.30). In comparison with other antimalarial drugs like quinine and chloroquine, clotrimazole shows better activity against chloroquine resistant malarial parasites because of its complex forming ability with free heme. Due to its poor and erratic bioavailability, Cmax is reached after 6 h when administered orally. The drug concentration for 50% inhibition of parasite was 0.2-1.1 µM and CLT at >2µM can cause complete inhibition of parasite replication. CLT is slightly basic in nature because of the presence of nitrogen atoms (pKa of N2 6.62; ChemAxon calculator). Clotrimazole is stable at pH 1.2, 4.5, 6.8, and 7.5 buffer solutions but it degrades in strongly acidic and basic media and at high temperature. The by-products obtained in strongly acidic medium are (o-chlorophenyl) diphenyl methanol and imidazole (Scheme 1).

Scheme 1 Degradation of Clotrimazole in Acidic Medium.
One important property associated with solid state forms of drug substances is their aqueous solubility. Compounds having poor water stability and solubility can lead to limited oral bioavailability when administered in patients, and therefore provision of new solid state forms of a pharmaceutically useful compound with better aqueous solubility provide a significant opportunity to increase the performance characteristics of the active pharmaceutical ingredient (API), such as oral bioavailability, flowability and solubility, which may cause reduction in the dosage required to be administered to the patient.
In the light of the better activity against chloroquine resistant malarial parasites and its poor aqueous solubility of clotrimazole, there remains a need in the art to provide novel solid forms of clotrimazole with good aqueous solubility, industrial feasibility and applicability with techno economic significance.

Object of the invention:
Accordingly, the main objective of this invention is to improve physicochemical properties of the antifungal drug Clotrimazole by providing novel solid forms so that it can be used as an oral formulation.

Summary of the invention:
In line with the above objective, the invention provides novel solid forms of Clotrimazole with biologically acceptable coformers.
In another aspect, the invention provides process for preparation of novel solid forms of Clotrimazole with biologically acceptable coformers. In one aspect, the novel solid form according to the invention is a salt of clotrimazole. In another aspect, the novel solid form of clotrimazole according to the invention is a cocrystal.
In yet another aspect, the invention provides novel solid forms of Clotrimazole with improved physicochemical properties of Clotrimazole such as solubility and dissolution.
In a further aspect, the invention provides pharmaceutical compositions comprising novel solid state forms of clotrimazole in association with one or more pharmaceutical excipients.

Brief description of the drawings:
Figure 1 depicts comparison of Powder pattern of CLT–ADA Cocrystal with Clotrimazole and adipic acid.
Figure 2 depicts comparison of PXRD pattern of CLT–SBA Cocrystal with starting materials.
Figure 3 depicts comparison of PXRD pattern of CLT–25DHBA Salt with Clotrimazole and 25DHBA powder patterns.
Figure 4 depicts comparison of PXRD pattern of CLT–246THBA Salt with starting materials showing changes in the resulting powder XRD pattern.
Figure 5 depicts comparison of PXRD pattern of CLT–CFA Salt with CLT and CFA powder XRD pattern.
Figure 6 depicts comparison of powder XRD pattern of CLT–PCA salt with the starting materials.
Figure 7 depicts comparison of PXRD pattern of CLT–MA salt with powder XRD pattern of CLT and MA.
Figure 8 depicts comparison of PXRD pattern of CLT–24DHBA salt with powder patterns of CLT and 24DHBA.
Figure 9 depicts comparison of PXRD pattern of CLT–26DHBA salt with powder XRD pattern of CLT and 26DHBA.
Figure 10 depicts comparison of PXRD pattern of CLT–34DHBA salt with powder XRD pattern of CLT and 34DHBA.
Figure 11 depicts comparison of PXRD pattern of CLT–35DHBA salt with powder XRD pattern of CLT and 35DHBA.
Figure 12 depicts intrinsic dissolution rate of CLT and its cocrystals and salts in 65% EtOH–H2O.
Figure 13 DSC thermogram of CLT salts/ cocrystals.
Figure 14 IR Comparison of CLT–246THBA salt with its starting materials.
Figure 15 IR comparison of CLT–25DHBA salt with its starting materials.
Figure 16 IR comparison of CLT–PCA salt with its starting materials.
Figure 17 IR comparison of CLT–CFA salt with its starting materials.
Figure 18 IR comparison of CLT–ADA cocrystal with its starting materials.
Figure 19 IR comparison of CLT–MA salt with its starting materials.
Figure 20 IR comparison of CLT–SBA cocrystal with its starting materials.
Figure 21 IR comparison of CLT–24DHBA salt with its starting materials.
Figure 22 IR comparison of CLT–26DHBA salt with its starting materials.
Figure 23 IR comparison of CLT–34DHBA cocrystal with its starting materials.
Figure 24 IR comparison of CLT–35DHBA cocrystal with its starting materials.
Figure 25 Solid-state 15N NMR chemical shift (ppm) values of CLT salts and cocrystals.
Figure 26 depicts X-ray crystal structure of CLT–25DHBA salt. Proton transferred from the carboxylic acid to the imidazole nitrogen of CLT. In the structure O–H???O hydrogen bond forming R2 2(14) motif and salt pairs extend through Cl???Cl (type-I) interactions.
Figure 27 depicts X-ray crystal structure of CLT–246THBA salt. In the structure, pairs of molecules extend through O–H???O bonds and the hydrogen-bonded chains extend in a wave manner with CLT hanging above and below the plane.
Figure 28 depicts X-ray crystal structure of CLT–PCA salt. In the crystal structure molecules bonded through N+–H???O– hydrogen bonds extend via C–H???Cl interactions.
Figure 29 depicts X-ray crystal structure of CLT–ADA cocrystal. Two molecules of CLT are connected to one molecule of adipic acid by O-H···N synthon. The chains extend via C-H···Cl interactions.
Figure 30 depicts X-ray crystal structure of CLT–CFA salt. CFA forms a tetramer R44(18) and R44 (38) ring motifs via O–H???O hydrogen bonds.
Abbreviations
CLT– Clotrimazole
ADA– Adipic acid
SBA– Suberic acid
2,5 DHBA– 2,5–Dihydroxybenzoic acid
2,4,6THBA– 2,4,6–Trihydroxybenzoic acid
CFA– Caffeic acid
PCA– p-Coumaric acid
MA– Maleic acid
2,4 DHBA– 2,4–Dihydroxybenzoic acid
2,6 DHBA– 2,6–Dihydroxybenzoic acid
3,4 DHBA– 3,4–Dihydroxybenzoic acid
3,5 DHBA– 3,5–Dihydroxybenzoic acid

Disclosure of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
In accordance with the above objective, the instant invention provides novel solid-state forms of Clotrimazole with biologically acceptable coformers.
In one embodiment, the novel solid form according to the invention is a pharmaceutical salt of clotrimazole. In another embodiment, the novel solid form of clotrimazole according to the invention is a pharmaceutical cocrystal.
In an embodiment, the present invention discloses the preparation of salts of Clotrimazole with 2,5-dihydroxy benzoic acid; 2,4,6-trihydroxy benzoic acid; para-coumaric acid; caffeic acid, maleic acid, 2,4-dihydroxy benzoic acid; 2,6-dihydroxy benzoic acid.
In an embodiment, the present invention discloses the preparation of cocrystals of Clotrimazole with adipic acid, suberic acid, 3,4-dihydroxy benzoic acid; and 3,5-dihydroxy benzoic acid.
In an embodiment, the present invention discloses improved solubility of Clotrimazole drug by making the pharmaceutical salts and cocrystals.
In an embodiment, the coformers used in the instant invention are provided in Scheme 2.
The novel solid forms of the present invention possess certain physical and chemical properties which render them particularly suitable for pharmaceutical development, such as good solubility, and bioavailability. In addition, they are suitable for bulk handling and formulation.
The clotrimazole salt and clotrimazole cocrystal may be differentiated by spectral data, specifically using PXRD and IR. As solid forms are reliably characterized by peak positions in the X-ray diffractogram, the solid forms of the present invention have been characterized by powder X-ray diffraction spectroscopy which produces a fingerprint of the particular crystalline form. Measurements of 2? values are accurate to within ± 0.2 degrees. Accordingly, all the solid forms of clotrimazole prepared according to the invention are characterized by PXRD as listed in Table 3.

Scheme 2 Molecular structures of the CLT and the list of coformers used in this study.
It will be appreciated that other conventional analytical methods including, but not limited to, IR, Mass, solid state NMR, Thermo gravimetric analysis (TGA), Differential Scanning Calorimetric analysis (DSC) and Raman spectroscopy may also be employed to characterize the solid forms of the clotrimazole of the present invention.
The melting points of the clotrimazole salt/ cocrystals as shown in Table 1 provided according to the invention are much lower than the individual counter parts, clotrimazole or its coformer. Accordingly, the melting points of clotrimazole salts/cocrystals with 2,5DHBA, CFA, PCA, 2,4,6 THBA, MA, SBA, 2,4 DHBA, 2,6 DHBA, 3,4 DHBA, and 3,5 DHBA are 154.5 °C, 141.1 °C, 170.3 °C, 150 °C, 122 °C, 130 °C, 110, 132 °C, 135-140 °C, 120 °C respectively.
From the solubility studies as depicted in Table 2, it is evident that the solubility of clotrimazole–MA salt is 22.45 times higher than that of the pure drug, while ADA and SBA cocrystals are higher by 5 times. Intrinsic dissolution was measured over a 4 h period to give values of 0.972 mg/ mL, 0.370 mg/ mL, 1.740 mg/ mL, and 1.658 mg/mL for CLT, CLT–ADA, CLT–MA, and CLT–SBA.
In yet another embodiment, the present invention discloses improved solubility and faster dissolution rate of Clotrimazole salts compared to the parent drug in 65% EtOH-H2O medium.
In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a solid form of clotrimazole consisting of clotrimazole and a GRAS conformer(s) selected from the group consisting of maleic acid, 2,5-dihydroxy benzoic acid, 2,4,6-trihydroxy benzoic acid, p-coumaric acid, caffeic acid, adipic acid, and suberic acid, optionally in association with one or more pharmaceutically acceptable excipients. The solid forms of clotrimazole according to the invention are selected from clotrimazole salt or clotrimazole co-crystal.
The selection of pharmaceutical excipients to prepare appropriate dosage forms using known and conventional methods can be done by skilled person using the solid forms of clotrimazole of the present invention. The selection of the excipients for example, rate retarding polymers, gelling polymers, binders, diluents, lubricants, disitegrants, fillers, coloring agents, flavouring agents etc, will vary and depend on the dosage form to be prepared.
In yet another aspect, the pharmaceutical compositions may be selected from the group consisting of tablets, capsules, in situ oral gels, topical gels, ointments, sprays, liquids, lotions, useful for the treatment of various fungal and parasitic diseases.
In a further aspect of the present invention, there is provided novel solid forms of clotrimazole for use in the treatment of chloroquine resistant malarial parasites.
In a further aspect of the present invention, there is provided novel solid forms of clotrimazole for use in the treatment of fungal infections.
In a further aspect of the present invention, there is provided method for the treatment of chloroquine resistant malarial parasites and fungal infections which method comprises administering novel solid forms of clotrimazole or pharmaceutical compositions comprising the same in association with one or more pharmaceutical excipients to a patient in need thereof. The pharmaceutical compositions may optionally comprise one or more other antimalarial agents selected from the group consisting of quinine and chloroquine compounds etc.
The quantity of the compound used in pharmaceutical compositions of the present invention will vary depending upon the body weight of the patient and the mode of administration and can be of any effective amount to achieve the desired therapeutic effect. The effective amount preferably varies from in the range of 0.01% to 99% of the dosage form and can be administered either once a day or twice a day.
The treatment regimen for the administration of the compound and/or compositions of the present invention can also be determined readily by those with ordinary skill in art depending on the severity of the disease condition of the patient. Particularly, the composition of the present invention can be administered as a unit dose either once a day or twice a day, to achieve the desired therapeutic effect.
The pharmaceutical composition according to the invention may be prepared as solid, liquid and gaseous forms using suitable excipients and by conventional manufacturing methods. The dosage forms may be administered in the form of tablets, capsules, liquids and suspensions.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Example 1
Preparation of cocrystals and salts
CLT–2,5 DHBA Salt (1:1) Clotrimazole and 2,5-dihydroxy benzoic acid were gently ground in equimolar (1:1) stoichiometry of CLT (344.83 mg, 1 mol) and 2, 5 DHBA (154.12 mg, 1 mol) in a mortar and pestle for 15 min using acetone as solvent. Single crystals for X-ray diffraction were obtained by dissolving the product in ethanol-anisole (1:1) solvent mixture and left for solvent evaporation.
CLT–2,4,6THBA Salt (1:1) Clotrimazole and 2, 4, 6-trihydroxybenzoic acid were ground in 1:1 stoichiometric ratio of CLT (344.83 mg, 1 mol) and 2,4,6 THBA (170.12 mg, 1 mol) in a mortar and pestle for 15 min using acetone as solvent. Colorless single crystals suitable for single crystal X-ray diffraction were obtained by dissolving the material in ethanol-anisole (1:1) solvent mixture left for solvent evaporation.
CLT–PCA Salt (1:1) Clotrimazole and p-coumaric acid salt were ground in 1:1 stoichiometry of CLT (344.83 mg, 1 mol) and PCA (164.16 mg, 1 mol) in a mortar and pestle for 15 min using acetone as solvent. Colorless single crystals suitable for single crystal X-ray diffraction were obtained by dissolving the material in ethanol-anisole (1:1) solvent mixture left for solvent evaporation.
CLT–ADA Cocrystal (1:0.5) Clotrimazole and adipic acid salt was obtained by grinding (1:0.5) stoichiometric ratio of CLT (344.83 mg, 1 mol) and ADA (73.07 mg, 1 mol) in a mortar and pestle for 15 min using acetone as solvent. Colorless single crystals suitable for single crystal X-ray diffraction were obtained by dissolving the material in ethanol-anisole (1:1) solvent mixture left for solvent evaporation.
CLT–CFA–ANI Salt Solvate (1:1:1) Clotrimazole and caffeic acid salt was obtained by grinding (1:1) stoichiometric ratio of CLT (344.83 mg, 1 mol) and CFA (180.16 mg, 1 mol) in a mortar and pestle for 15 min using acetone as solvent. Colorless single crystals suitable for crystal X-ray diffraction were obtained by dissolving the material in ethanol-anisole (1:1) solvent mixture left for solvent evaporation. The product was characterized as Clotrimazole–Caffeine–Anisole solvate by X-ray diffraction.
CLT-SBA Cocrystal (1:0.5) Clotrimazole and suberic acid salt was obtained by grinding (1:0.5) stoichiometric ratio of CLT (344.83 mg, 1 mol) and SBA (87.1 mg, 1 mol) in a mortar and pestle for 15 min using acetone as solvent.
CLT-MA Salt (1:0.5) Clotrimazole and maleic acid salt was obtained by grinding (1:0.5) stoichiometric ratio of CLT (344.83 mg, 1 mol) and MA (58.03 mg, 1 mol) in a mortar and pestle for 15 min using acetone as solvent.
CLT–2,4 DHBA Salt (1:1) Clotrimazole and 2,4-dihydroxy benzoic acid were gently ground in equimolar (1:1) stoichiometry of CLT (344.83 mg, 1 mol) and 2,4 DHBA (154.12 mg, 1 mol) in a mortar and pestle for 15 min using acetone as solvent. The resulted salt was confirmed changes in the powder pattern from parent compounds and FT-IR spectroscopy.
CLT–2,6 DHBA Salt (1:1) Clotrimazole and 2,6-dihydroxy benzoic acid were gently ground in equimolar (1:1) stoichiometry of CLT (344.83 mg, 1 mol) and 2,6 DHBA (154.12 mg, 1 mol) in a mortar and pestle for 15 min using acetone as solvent. The resulted salt was confirmed changes in the powder pattern from parent compounds and FT-IR Spectroscopy.
CLT–3,4 DHBA Cocrystal (1:1) Clotrimazole and 3,4-dihydroxy benzoic acid were gently ground in equimolar (1:1) stoichiometry of CLT (344.83 mg, 1 mol) and 3,4 DHBA (154.12 mg, 1 mol) in a mortar and pestle for 15 min using acetone as solvent.
CLT–3,5 DHBA Salt (1:1) Clotrimazole and 3,5-dihydroxy benzoic acid were gently ground in equimolar (1:1) stoichiometry of CLT (344.83 mg, 1 mol) and 3,5 DHBA (154.12 mg, 1 mol) in a mortar and pestle for 15 min using acetone as solvent.
Example 2
(a) X-ray Powder Diffraction (XRPD)
Powder X-Ray Diffraction technique is a nondestructive technique, having wide range of applications in pharmaceutical industries. It is mainly used to know the bulk purity of resulting material. In the present investigation powder patterns for all the compounds were recorded on SMART Bruker D8 Focus Powder X-ray diffractometer using Cu-Ka radiation (? = 1.5406 Å) at 40 kV and 30 mA. Overlay of the experimental powder XRD pattern on the calculated lines for the crystal structure confirms purity and homogeneity of the bulk phase for CLT–ADA, CLT–25DHBA, CLT–246THBA, CLT–PCA, CLT–CFA, CLT–24DHBA, CLT–26DHBA, CLT–34DHBA, and CLT–35DHBA. CLT–CFA was crystallized from anisole–EtOH solvent mixture and it included anisole in the crystal lattice to give CLT–CFA–ANI. Microcrystalline powder of CLT–MA and CLT–SBA was obtained from acetone by grinding for about 20 min but good quality single crystals did not develop from the solvent. The difference in powder pattern compared to starting materials means the formation of a novel solid form.
(b) Single crystal X-ray diffraction:
X-ray reflections for the CLT-ADA, CLT–2,5DHBA, and CLT–PCA were collected on Oxford Xcalibur Gemini Eos CCD diffractometer at 298 K using Mo-Ka radiation (? = 0.7107 Å). Data reduction was performed using CrysAlisPro (version1.171.33.55) and OLEX2 was to solve and refine the structures. X-ray reflections for CLT-246 THBA and CLT-CFA were collected on Bruker SMART-APEX CCD diffractometer equipped with a graphite monochromator and Mo-Ka fine-focus sealed tube (? = 0.71073 Å). Data reduction was performed using Bruker SAINT Software. Intensities were corrected for absorption using SADABS, and the structure was solved and refined using SHELX-97 (SMART, version 5.625 and SHELX-TL, version 6.12; Bruker AXS Inc., Madison, Wisconsin, USA, 2000). All non-hydrogen atoms were refined anisotropically. Hydrogen atoms on hetero atoms were located from difference electron density maps and all C-H hydrogens were fixed geometrically. Hydrogen bond geometries were determined in Platon. X-Seed (Barbour, L. J. X-Seed, Graphical Interface to SHELX-97 and POV-Ray, Program for Better Quality of Crystallographic Figures, University of Missouri-Columbia, Missouri, 1999) was used to prepare packing diagrams.
CLT–2,5 DHBA (1:1) salt This salt was prepared by taking equimolar amount of the components in CHCl3-EtOH (1:1) and the crystal structure was solved in space group P-1. The structure contains one CLT–NH+ cation and 25DHBA? anion through proton transfer from 25DHBA to the imidazole N2 of CLT (N2–H2A???O1: 1.8 ?, 169°). The phenolic hydroxy group ortho to the acid group is involved in intramolecular hydrogen bond (O3–H3A???O1: 1.85 ?, 146°) and the second hydroxy group interacts with O2 (carboxylate) of adjacent 25DHBA? (O4–H4A???O2: 1.91 ?, 168°) in a R2 2(14) dimer ring motif. Auxiliary C–H???O (2.46 ?, 152°; 2.56 ?, 139°) and weak Cl???Cl interactions stabilize the structure.
CLT–2,4,6 THBA Salt (1:1) The title salt was prepared in bulk by liquid-assisted grinding of CLT and 246THBA in equimolar ratio from acetone. Single crystals were harvested from CHCl3-EtOH (1:1) and the crystal structure (P21/n space group) confirms CLT–NH+ and 246THBA? ions in the asymmetric unit, with the proton being transferred to the basic N2 of CLT (N2–H2A???O1: 1.73 ?, 173°). The intra molecular hydrogen bonds (O3–H3A???O2: 1.67 ?, 152°; O4–H4A???O1: 1.69 ?, 151°) and the p-hydroxyl donor makes intermolecular hydrogen bond with the carboxylate (O5–H5A???O2: 1.81 ?, 174°) to make a wave-like arrangement. Coformer acid molecules are arranged in a corrugated sheet and CLT molecules hang on alternately through N2–H2A???O1 bond. The chains extend via C–H???O interactions (2.57 ?, 145°; 2.58 ?, 141°).
CLT–PCA Salt (1:1) Single crystals of CLT–PCA (1:1) salt were obtained from CHCl3 and the structure was determined in space group P212121. The crystal structure contains one molecule of each ion in the asymmetric unit. Similar to above salts, CLT–NH+ and PCA? ions are bonded through ionic N2–H2A???O3 (1.78 ?, 161°). The acid moieties extend via O1–H1A???O2 (1.90 ?, 174°) and C27–H27???O2 (2.49 ?, 130°) interactions in a 1D tape and further by C10–H10???Cl1 (2.73 ?, 161°) interaction at the chlorine atom of CLT.
CLT–ADA cocrystal (1:0.5) The ground material of CLT and ADA in stoichiometric ratio (1:0.5) was crystallized from EtOH. The same cocrystal structure in P-1 space group was obtained by crystallization of the cocrystal powder from EtOH–CHCl3. One CLT and half diacid molecule are present in the asymmetric unit. The protons of ADA are hydrogen bonded to imidazole nitrogen of CLT (O1–H1A???N2: 1.84 ?, 174°). Bifurcated C–H???O interactions connect CLT to carbonyl oxygen (O2) and dimeric C-H···Cl interactions.
CLT-CFA Salt This salt was prepared by liquid-assisted grinding using equimolar CLT and caffeic acid the product was characterized by powder XRD, IR. The product was recrystallized from anisole-ethanol P21/c space group. Anisole molecule was included in the crystal lattice CLT–CFA–ANI (1:1:1) to give CLT–NH+, CFA? and anisole. A proton is transferred from CFA to imidazole N2 of CLT (N2–H2A???O3: 1.80 ?, 172°). The acid forms two types of tetrameric units, R44(18) and R44 (38) ring motif via O1–H1A???O3 (1.95 ?, 149°), O2–H2C???O4 (1.82 ?, 161°) H bonds and CLT–NH+ ions are arranged alternately above and the below the plane of acid tetramers sustained by ionic N2–H2A???O3 bonds. The oxygen of carboxyl group forms bifurcated O–H???O and N–H???O motif with the OH group of CFA and NH donor of CLT.
Infrared Spectroscopy
In CLT salts, a proton is transferred from the coformer acid to the imidazole nitrogen (N2) of CLT. Normally free COOH group stretching frequency occurs at 1730–1700 cm-1 and COO– group absorbs strongly at 1640–1540 cm-1 (asym). The C=N absorption peak of CLT appears at 1646.7 cm-1 and for salts a bathochromic shift is observed with respective to the acid coformer. In ADA cocrystal and MA salt there is significant increase in absorption of N–H stretching frequency at 3400–3500 cm-1. The COO– stretching (asym) and N–H bending frequencies are very close in values, and so it is quite difficult to differentiate between them.
Thermal analysis DSC is a thermo analytical technique in which amount of heat energy difference required to increase the temperature of a sample compared to null reference is measured as a function of temperature. Clotrimazole showed a sharp endotherm at 148 °C without any phase transformation. The ground material of CLT and ADA cocrystal melts at 134.9 °C (M.p. adipic acid 151-153 °C). The melting points of other CLT salts with 25DHBA, CFA, PCA, 246THBA, MA, 24DHBA, and 26DHBA, are 154.5 °C, 141.1 °C, 170.3 °C, 150 °C, 122 °C, 110, 132 °C and melting points of other cocrystals of CLT with SBA, 34DHBA, 35DHBA are 130 °C, 135-140 °C, 120°C.

Table 1 Melting point of salts and cocrystals.
Sr. No. Compound Melting point of API/Coformer (° C) Melting Point of cocrystal/salt (° C)
1 CLT 148 ---
2 CLT–ADA (1:0.5) 152 134.9
3 CLT–2,5 DHBA (1:1) 203 154.5
4 CLT–CFA (1:1) 223 141.1
5 CLT–PCA (1:1) 211 170.3
6 CLT–SBA (1:0.5) 142 130.0
7 CLT–2,4,6 THBA (1:1) 210 150.0
8 CLT–MA (1:0.5) 135 122.0
9 CLT–2,4 DHBA (1:1) 208-211 110
10 CLT–2,6 DHBA (1:1) 165 132
11 CLT–3,4 DHBA (1:1) 202-204 135-140
12 CLT–3,5 DHBA (1:1) 236-238 120

Example 3
Solubility and Dissolution
Poor solubility is the major issue in the pharmaceutical industry for many drugs because poor pharmacokinetic and pharmaco-dynamic properties limit bioavailability. Improvement in dissolution rate and solubility by means of supramolecular modification of an API is a crystal engineering strategy. The solubility curves of CLT (a BCS Class II drug) and its salts and cocrystal (CLT–ADA, CLT–MA, CLT–SBA) were measured using the Higuchi and Connor method in 65% ethanol-water medium (due to poor aqueous solubility of CLT=0.49 µg/mL) at 37 °C. First, the absorbance of a known concentration of the salt was measured at the given ?max (CLT at 262 nm) in 65% ethanol-water medium on Thermo Scientific Evolution 300 UV-vis spectrometer (Thermo Scientific, Waltham, MA). These absorbance values were plotted against several known concentrations to prepare the concentration vs. intensity calibration curve. From the slope of the calibration curves, molar extinction coefficients for CLT salts were calculated and the respective molar extinction coefficients 1.609, 0.75, 1.0, and 0.563 are used to determine the intrinsic dissolution. An excess amount of the sample was added to 6 mL of 65% ethanol-water medium. The supersaturated solution was stirred at 500 rpm using a magnetic stirrer at 30 °C. After 24 h, the suspension was filtered through Whatman’s 0.45µm syringe filter. The filtered aliquots were diluted sufficiently, and the absorbance was measured at the given ?max. In the case of CLT–CFA, CLT–2,5 DHBA, CLT–2,4,6 THBA, and CLT–PCA, the coformer absorption interferes with that of CLT (at 262 nm) due to the aromatic ring in the coformer acid. Hence the solubility of these salts was determined by analytical HPLC using acetonitrile and 1% acetic acid as the mobile phase (1:1 v/v). The intrinsic dissolution studies of CLT salts was done using CLT 100 mg, CLT–MA 100 mg, CLT–SBA 100 mg, and CLT–ADA 100 mg (0.289, 0.248, 0.231, 0.239 mol of each compound). This was directly poured into 500 mL 65% ethanol-water medium. The paddle rotation was fixed at 150 rpm and dissolution experiments were continued up to 240 min at 37 ºC. At regular intervals, 5 mL of the dissolution medium was withdrawn and replaced by an equal volume of fresh medium to maintain a constant volume. The AUC was calculated using the linear trapezoidal rule of drug bioavailability. The nature of the solid samples after disk compression and solubility/dissolution measurements was verified by PXRD to know if there is any phase transition. From our studies the solubility of CLT–MA salt is 22.45 times higher than that of the pure drug, while ADA and SBA cocrystals were higher by 5 times. Intrinsic dissolution was measured over a 4 h period to give values of 0.972 mg/ mL, 0.370 mg/ mL, 1.740 mg/ mL, and 1.658 mg/mL for CLT, CLT–ADA, CLT– MA, and CLT– SBA.

Table 2 Intrinsic dissolution rate and solubility of CLT cocrystal/salts.
Compound Molar extinction coefficient,
? /mM cm Equilibrium
Solubility (mg/L) Solution concentration in mg/mL (240 min) Area under the curve,
AUC 0–4 h (mg h)/L
CLT 1.609 4.40 0.972 427
CLT–ADA 0.750 22.06 (×5.0) 0.370 234.58
CLT–MA 1.000 98.79 (×22.43) 1.740 1233.82
CLT–SBA 0.563 22.01 (×4.99) 1.658 867.23
CLT–2,4,6 THBA -- 61.87 (×14.04) --
CLT–2,5 DHBA -- 13.11 (×2.97) --
CLT–PCA -- 5.84 (×1.32) --
CLT–CFA -- 12.48 (×2.83) --

Table 3 PXRD 2 theta (deg) and relative peak intensity of Clotrimazole and its salts/cocrystals.
CLT CLT–ADA CLT–SBA
Angle d Value Relative Intensity Angle d Value Relative Intensity Angle d Value Relative Intensity
9.222 9.582 100.0% 9.316 9.486 19.6% 6.943 12.721 1.2%
9.857 8.966 43.2% 9.572 9.232 34.3% 8.738 10.112 50.5%
10.269 8.607 7.6% 9.898 8.929 10.3% 9.290 9.512 33.5%
12.435 7.113 86.5% 10.242 8.630 7.3% 9.937 8.894 30.3%
14.265 6.204 12.7% 11.177 7.910 32.7% 10.980 8.051 100.0%
15.239 5.809 3.8% 11.257 7.854 45.9% 12.459 7.099 33.7%
15.695 5.642 3.4% 12.127 7.292 5.9% 13.327 6.638 18.5%
16.772 5.282 18.7% 12.444 7.108 26.4% 13.609 6.502 69.4%
18.647 4.755 49.6% 13.360 6.622 59.2% 14.295 6.191 29.6%
19.469 4.556 39.4% 14.345 6.170 2.6% 15.226 5.814 2.6%
19.927 4.452 22.4% 14.951 5.921 9.7% 16.196 5.468 20.9%
20.718 4.284 33.4% 15.609 5.673 23.6% 16.218 5.461 22.6%
22.599 3.931 19.3% 16.882 5.247 26.6% 16.685 5.309 39.2%
23.112 3.845 21.8% 16.692 5.307 13.9% 17.553 5.048 57.3%
24.271 3.664 18.1% 16.989 5.215 27.1% 17.430 5.084 29.3%
25.185 3.533 19.9% 18.295 4.845 11.8% 18.729 4.734 17.8%
25.590 3.478 11.8% 18.654 4.753 100.0% 19.083 4.647 41.2%
26.215 3.397 6.3% 19.338 4.586 46.5% 19.539 4.540 19.9%
27.556 3.234 16.8% 20.275 4.377 16.0% 20.015 4.433 32.9%
28.187 3.163 22.6% 21.081 4.211 70.4% 20.965 4.234 38.6%
28.868 3.090 5.7% 21.462 4.137 82.0% 21.489 4.132 23.1%
31.128 2.871 4.5% 21.746 4.084 9.3% 22.376 3.970 67.7%
31.870 2.806 7.5% 22.639 3.924 11.0% 23.113 3.845 17.6%
32.746 2.733 11.8% 23.072 3.852 34.5% 24.092 3.691 7.3%
33.506 2.672 0.8% 23.654 3.758 29.8% 24.750 3.594 13.3%
34.565 2.593 6.4% 24.171 3.679 17.8% 25.450 3.497 8.5%
34.619 2.589 7.2% 25.530 3.486 20.2% 25.863 3.442 16.8%
35.794 2.507 1.6% 25.996 3.425 31.7% 26.231 3.395 28.1%
37.211 2.414 3.3% 26.753 3.330 34.8% 26.823 3.321 17.0%
37.707 2.384 4.4% 27.015 3.298 23.0% 27.055 3.293 16.1%
38.562 2.333 2.7% 27.553 3.235 4.9% 27.578 3.232 5.5%
39.517 2.279 1.0% 28.065 3.177 10.1% 28.102 3.173 11.4%
40.366 2.233 2.3% 29.168 3.059 8.9% 28.621 3.116 5.6%
30.400 2.938 1.1% 29.108 3.065 7.9%
31.135 2.870 13.9% 29.841 2.992 2.6%
31.752 2.816 8.5% 30.508 2.928 5.0%
CLT–2,5 DHBA CLT–246THBA CLT–PCA
Angle d Value Relative Intensity Angle d Value Relative Intensity Angle d Value Relative Intensity
7.522 11.744 57.1% 8.408 10.507 38.6% 7.856 11.244 17.7%
9.400 9.401 100.0% 9.667 9.142 28.7% 9.939 8.892 6.7%
9.932 8.899 7.2% 11.016 8.025 100.0% 10.563 8.368 96.9%
10.483 8.432 26.9% 12.720 6.954 38.0% 11.558 7.650 42.5%
12.650 6.992 29.8% 13.878 6.376 6.1% 12.820 6.900 3.8%
13.247 6.678 18.2% 14.702 6.020 44.6% 14.506 6.102 25.4%
14.234 6.217 28.1% 15.502 5.712 3.5% 15.413 5.744 35.7%
14.854 5.959 17.8% 16.042 5.521 9.4% 16.967 5.222 56.8%
16.364 5.413 25.8% 17.209 5.149 23.6% 18.009 4.922 12.6%
16.211 5.463 18.0% 19.189 4.622 24.4% 18.820 4.711 22.7%
17.407 5.091 20.5% 19.534 4.541 23.3% 19.642 4.516 11.3%
18.078 4.903 43.2% 19.991 4.438 17.2% 20.785 4.270 33.0%
18.934 4.683 54.7% 20.730 4.281 55.8% 21.344 4.160 92.7%
20.994 4.228 61.3% 22.171 4.006 13.1% 22.241 3.994 100.0%
21.065 4.214 85.9% 23.141 3.840 19.8% 23.541 3.776 4.1%
22.228 3.996 28.9% 23.492 3.784 35.1% 24.250 3.667 11.9%
22.882 3.883 44.1% 24.382 3.648 11.0% 25.476 3.494 8.2%
24.865 3.578 24.6% 25.170 3.535 10.4% 26.048 3.418 10.4%
25.556 3.483 29.4% 25.511 3.489 18.0% 26.202 3.398 11.2%
26.501 3.361 9.7% 25.886 3.439 20.8% 26.972 3.303 3.9%
27.496 3.241 28.7% 26.952 3.305 10.1% 27.456 3.246 11.9%
27.634 3.225 26.4% 27.755 3.212 2.6% 28.079 3.175 11.9%
28.921 3.085 15.2% 28.710 3.107 2.9% 29.338 3.042 9.7%
29.891 2.987 7.8% 29.349 3.041 12.0% 30.419 2.936 6.0%
31.250 2.860 2.7% 30.664 2.913 4.5%
30.698 2.910 4.3%
CLT–CFA CLT–MA
Angle d Value Relative Intensity Angle d Value Relative Intensity
7.781 11.352 8.4% 9.220 9.584 82.5%
8.574 10.304 1.5% 9.852 8.971 76.0%
9.480 9.322 10.2% 10.308 8.575 9.9%
10.035 8.808 26.7% 10.557 8.373 11.6%
10.576 8.358 15.6% 11.271 7.844 51.4%
12.250 7.220 2.7% 12.435 7.112 100.0%
12.632 7.002 11.8% 12.839 6.889 27.3%
13.507 6.550 15.3% 14.221 6.223 26.4%
14.218 6.224 26.4% 15.153 5.842 17.0%
14.860 5.957 23.5% 15.707 5.637 1.3%
15.555 5.692 8.8% 16.777 5.280 35.6%
15.971 5.545 35.3% 17.143 5.168 23.4%
17.103 5.180 4.6% 17.301 5.121 10.2%
17.650 5.021 39.7% 18.522 4.787 54.6%
18.920 4.687 8.2% 19.534 4.541 52.4%
19.321 4.590 14.3% 20.062 4.422 60.8%
20.096 4.415 56.0% 20.034 4.429 60.2%
21.254 4.177 100.0% 20.703 4.287 64.9%
22.428 3.961 40.0% 21.655 4.100 76.8%
22.863 3.886 12.6% 22.796 3.898 60.5%
23.741 3.745 10.5% 23.775 3.739 14.1%
24.683 3.604 32.9% 24.392 3.646 33.5%
24.545 3.624 35.7% 24.669 3.606 26.4%
25.702 3.463 15.5% 25.155 3.537 28.6%
25.910 3.436 51.2% 25.619 3.474 21.9%
26.901 3.312 24.4% 26.243 3.393 10.6%
27.193 3.277 68.7% 26.967 3.304 6.2%
28.366 3.144 21.2% 27.482 3.243 30.6%
28.861 3.091 8.1% 28.273 3.154 60.2%
29.786 2.997 2.9% 29.682 3.007 3.1%
30.169 2.960 10.5% 30.591 2.920 6.5%

CLT–2,4 DHBA CLT-2,6 DHBA CLT-3,4 DHBA
Angle d Value Relative Intensity Angle d Value Relative Intensity Angle d Value Relative Intensity
7.444 11.865 0% 8.419 10.494 6% 6.757 13.072 39%
8.500 10.394 58% 8.937 9.887 40% 9.288 9.514 18%
9.482 9.320 67% 9.940 8.892 100% 9.763 9.052 2%
11.258 7.853 100% 10.533 8.392 8% 11.279 7.839 31%
12.904 6.855 39% 12.017 7.359 50% 11.647 7.592 1%
14.233 6.218 49% 13.554 6.528 94% 12.787 6.917 68%
15.505 5.710 18% 14.827 5.970 1% 13.521 6.544 4%
15.920 5.562 9% 16.330 5.424 19% 14.522 6.095 63%
17.148 5.167 4% 16.805 5.272 16% 14.870 5.953 53%
17.673 5.014 31% 17.828 4.971 19% 15.859 5.584 33%
19.018 4.663 49% 18.537 4.783 17% 16.299 5.434 58%
20.078 4.419 35% 19.910 4.456 60% 18.122 4.891 21%
21.165 4.194 11% 20.516 4.325 90% 18.663 4.751 23%
21.511 4.128 29% 21.037 4.220 23% 19.386 4.575 21%
23.031 3.859 40% 21.870 4.061 77% 19.750 4.492 21%
24.021 3.702 17% 22.600 3.931 49% 20.358 4.359 20%
25.192 3.532 11% 23.426 3.794 14% 21.420 4.145 56%
25.998 3.425 24% 24.385 3.647 9% 22.329 3.978 63%
26.365 3.378 14% 25.281 3.520 12% 22.602 3.931 10%
27.260 3.269 12% 25.842 3.445 29% 23.203 3.830 20%
28.060 3.177 7% 26.655 3.342 19% 24.149 3.682 44%
28.777 3.100 23% 26.912 3.310 26% 24.997 3.559 100%
29.194 3.057 5% 28.008 3.183 4% 25.755 3.456 5%
30.438 2.934 3% 28.791 3.098 3% 26.561 3.353 16%
29.507 3.025 9% 27.078 3.290 10%
30.301 2.947 16% 27.392 3.253 26%
27.797 3.207 36%
27.851 3.201 32%
28.881 3.089 22%
30.039 2.972 3%
30.68515 2.9113 4%

Example 4
In situ-gel for oral drug delivery:
Clotrimazole salt-0.1%
Carbopol 934P -0.1-1.6% w/v,
Hydroxylpropyl methylcelluose E50LV -0.5-1%,
Sodium citrate -0.17% w/v, and
Calcium chloride -0.05% w/v
Deionized water-Q.S
Clotrimazole salt as referred above may be selected from the group consisting of Clotrimazole-2,5 DHBA salt; Clotrimazole-2,4,6 THBA salt; Clotrimazole-PCA salt; Clotrimazole-CFA salt; Clotrimazole-MA salt; Clotrimazole-2,4 DHBA salt; and Clotrimazole-2,6 DHBA salt.
Procedure:
The insitu gel for oral delivery can be prepared by the known methods reported in the art (Indian J Pharm Sci. 2009 Jul-Aug; 71(4): 421–427). Accordingly, varying concentration containing Carbopol 934P or HPMC (E50LV) that exhibit phase transition due to the changes in physico-chemical environments such as pH, were prepared by dissolving in phosphate buffer pH 4.5. To this solution, added sodium citrate and heated to an elevated temperature of 70 to 95° C under stirring. After cooling to room temperature, appropriate amount of calcium chloride was added into the sol. Clotrimazole salt(s) prepared in accordance with the invention was dissolved in aq. ethanol (2% w/w) and was added to the sol. The mixture was stirred by using a magnetic stirrer to ensure thorough mixing. The pH of the gel obtained was in the range of 6.5 to 7.0.

Example 5
Clotrimazole salt-0.1%
Gellan gum -0.5 to 1.0% w/v,
hydroxylpropylmethylcelluose E50LV -0.5-1%,
Sodium citrate -0.17% w/v, and
Calcium chloride -0.05% w/v
Deionized water-Q.S
Clotrimazole salt as referred above may be selected from the group consisting of Clotrimazole-2,5 DHBA salt; Clotrimazole-2,4,6 THBA salt; Clotrimazole-PCA salt; Clotrimazole-CFA salt; Clotrimazole-MA salt; Clotrimazole-2,4 DHBA salt; and Clotrimazole-2,6 DHBA salt.

Procedure for preparation of the in situ gels for oral delivery:
The insitu gel for oral delivery can be prepared by the known methods reported in the art (Indian J Pharm Sci. 2009 Jul-Aug; 71(4): 421–427). Accordingly, varying concentration containing gellan gum or any other suitable gels that exhibit phase transition due to the changes in physico-chemical environments such as pH, were prepared by dissolving in de-ionized water. To this solution, added sodium citrate and heated to an elevated temperature of 70 to 95° C under stirring. After cooling to room temperature, appropriate amount of calcium chloride was added into the sol. Clotrimazole salt(s) prepared in accordance with the invention was dissolved in aq. ethanol (2% w/w) and was added to the sol. The mixture was stirred by using a magnetic stirrer to ensure thorough mixing. The pH of the gel obtained was in the range of 6.5 to 7.0.
Alternately, the formulations of insitu-gels for oral drug delivery as provided above under examples 1 & 2 can also be prepared with clotrimazole cocrystals in accordance with the invention selected from the group consisting of Clotrimazole-SBA cocrystal; Clotrimazole-ADA cocrystal; Clotrimazole-3,4 DHBA cocrystal; and Clotrimazole-3,5 DHBA cocrystal.

Example 6
Gel for topical drug delivery:
Clotrimazole salt -0.1%
Menthol-1%
Gelling solvent (methyl salicylate or toluene)- 0.5 mL
Clotrimazole salt as referred above may be selected from the group consisting of Clotrimazole-2,5 DHBA salt; Clotrimazole-2,4,6 THBA salt; Clotrimazole-PCA salt; Clotrimazole-CFA salt; Clotrimazole-MA salt; Clotrimazole-2,4 DHBA salt; and Clotrimazole-2,6 DHBA salt.
Alternately, the formulation of gels for topical drug delivery can also be prepared with clotrimazole cocrystals in accordance with the invention selected from the group consisting of Clotrimazole-SBA cocrystal; Clotrimazole-ADA cocrystal; Clotrimazole-3,4 DHBA cocrystal; and Clotrimazole-3,5 DHBA cocrystal.

Procedure for preparation of gel for topical delivery:
To prepare gel for topical delivery, 2mg (weight can vary) of Clotrimazole salt/cocrystals and 20mg menthol (weight can vary) were dissolved in 0.5 mL gelling solvent (methyl salicylate/ethanol) by heating around 60-70 °C and the hot clear solution was then allowed to cool to room temperature to afford stable gel within a few minutes. Gel formation was confirmed by test tube inversion method.
,CLAIMS:1. Novel solid forms of clotrimazole comprising clotrimazole and a GRAS conformers selected from the group consisting of maleic acid, 2,5-dihydroxy benzoic acid, 2,4,6-trihydroxy benzoic acid, p-coumaric acid, caffeic acid, adipic acid, and suberic acid.
2. The solid forms of clotrimazole according to Claim 1, wherein, the solid forms are selected from clotrimazole salt or clotrimazole cocrystal.
3. The solid forms of clotrimazole according to Claim 2, wherein, the clotrimazole salts are selected from the group consisting of Clotrimazole-2,5 DHBA salt; Clotrimazole-2,4,6 THBA salt; Clotrimazole-PCA salt; Clotrimazole-CFA salt; Clotrimazole-MA salt; Clotrimazole-2,4 DHBA salt; and Clotrimazole-2,6 DHBA salt.
4. The solid forms of clotrimazole according to Claim 2, wherein, the clotrimazole cocrystals are selected from the group consisting of Clotrimazole-SBA cocrystal; Clotrimazole-ADA cocrystal; Clotrimazole-3,4 DHBA cocrystal; and Clotrimazole-3,5 DHBA cocrystal.
5. The solid forms of clotrimazole according to Claim 3, wherein, the Clotrimazole-2,5 DHBA salt is characterized by (i) PXRD and characteristic peaks at 2? 9.4, 12.6, 14.8, 21.0, and 24.8 deg, (ii) DSC endotherm at 154.5 °C, (iii) In infrared spectroscopy peaks at 1618.3 cm-1 (for C=N), 3426.2 cm-1 (for N–H stretch) and finally salt structure was confirmed by single crystal X-ray diffraction with cell parameters a = 10.1 Å, b = 10.6 Å, c = 13.0 Å, a = 108.4°, ? = 102.9°, ? = 107.0°, Vol. = 1200 Å3.
6. The solid forms of clotrimazole according to Claim 3, wherein Clotrimazole-2,4,6 THBA salt is characterized by (i) PXRD at 2? 8.4, 9.6, 11,0, 17.2, 19.1, and 20.7 deg ii) DSC single endotherm at 150.0 °C, (iii) In infrared spectroscopy peaks at 1634.7 cm-1 (for C=N), 3449.3 cm-1 (for N-H stretch) and finally confirmed by single crystal X-ray diffraction with cell parameters a = 12.0 Å, b = 13.8 Å, c = 15.9 Å, a = 90°, ? = 97.9°, ? = 90°, Vol. = 2630 Å3.
7. The solid forms of clotrimazole according to Claim 3, wherein Clotrimazole-PCA salt is characterized by (i) PXRD and characteristic peaks at 2? 7.8, 10.5, 11.5, 14.5, 16.9, 21.3, and 22.2 deg (ii) DSC endotherm at 170.3 °C, (iii) In infrared spectroscopy peaks at 1604.3 cm-1 (for C=N), 3453.4 cm-1 (for N-H stretch) and finally structure confirmed by single crystal X-ray diffraction with cell parameters a = 10.3 Å, b = 14.9 Å, c = 16.4 Å, a = 90°, ? = 90°, ? = 90°, Vol. = 2552 Å3.
8. The solid forms of clotrimazole according to Claim 3, wherein Clotrimazole-CFA salt is characterized by (i) PXRD and characteristic peak at 2? 10.0, 13.5, 14.8, 17.6, 20.0, 21.2, 22.4, and 27.1 deg (ii) DSC endotherm at 141 °C, (iii) In infrared spectroscopy peaks at 1640.4 cm-1 (for C=N), 3437.6 cm-1 (for N-H stretch) and finally structure confirmed by single crystal X-ray diffraction with cell parameters a = 12.4 Å, b = 14.5 Å, c = 17.7 Å, a = 90°, ? = 96°, ? = 90°, Vol. = 3211 Å3.
9. The solid forms of clotrimazole according to Claim 3, wherein Clotrimazole-MA salt is characterized by (i) PXRD and characteristic peaks at 2? 9.2, 9.8, 11.2, 12.4, 12.8, 18.5, 19.5, 20.0, 21.6, and 22.7 deg, (ii) DSC endotherm at 122 °C, and (iii) In infrared spectroscopy peaks at 1701.8 cm-1 (for C=N), 3483.1 cm-1 (for N-H stretch).
10. The solid forms of clotrimazole according to Claim 4, wherein Clotrimazole-SBA cocrystal is characterized by (i) PXRD characteristic peaks at 2? 8.7, 9.2, 10.9, 13.6, 16.2, 23.3, and 24.7 deg, (ii) DSC endotherm at 130.0 °C and (iii) In infrared spectroscopy characteristic peak observed at 1699.0 cm-1 (for C=N).
11. The solid forms of clotrimazole according to Claim 4, wherein Clotrimazole-ADA cocrystal is characterized by (i) PXRD and characteristic peaks at 2? 9.5, 10.2, 11.1, 11.2, 13.3, 18.6, 21,0, and 26.7 deg, (ii) DSC endotherm at 134.9 °C, (iii) In infrared spectroscopy peaks at 1694.5 cm-1 (for C=N) and finally structure confirmed by single crystal X-ray diffraction with cell parameters a = 8.7 Å, b = 9.6 Å, c = 13.2 Å, a = 74.4°, ? = 84.2°, ? = 85.4°, Vol. = 1069.4 Å3.
12. The solid forms of clotrimazole according to Claim 3, wherein Clotrimazole-2,4 DHBA salt is characterized by (i) PXRD at 2? 8.5, 11.2, 17.1, 17.6, and 21.5 deg ii) Melting at 110 °C, and (iii) In infrared spectroscopy peaks at 1632.2 cm-1 (for C=N), 3376.6 cm-1 (for N-H stretch).
13. The solid forms of clotrimazole according to Claim 3, wherein Clotrimazole-2,6 DHBA salt is characterized by (i) PXRD at 2? 8.9, 9.9, 13.5, 17.6, 21.8 and 22.6 deg ii) Melting at 132 °C, and (iii) In infrared spectroscopy peaks at 1632.2 cm-1 (for C=N), 3155 cm-1 (for N-H stretch).
14. The solid forms of clotrimazole according to Claim 4, wherein Clotrimazole-3,4 DHBA cocrystal is characterized by (i) PXRD and characteristic peaks at 2? 6.7, 9.7, 11.6, and 12.7 deg, (ii) Melting at 135-140 °C and (iii) infrared spectrum peaks at 1674.5 cm-1 (for C=N).
15. The solid forms of clotrimazole according to Claim 4, wherein Clotrimazole-35DHBA cocrystal is characterized by (i) PXRD where the resulted material is amorphous (ii) infrared spectroscopy peaks at 1689.6 cm-1 (for C=N).
16. A pharmaceutical composition comprising solid form of clotrimazole consisting of clotrimazole and a GRAS conformers selected from the group consisting of maleic acid, 2,5-dihydroxy benzoic acid, 2,4,6-trihydroxy benzoic acid, p-coumaric acid, caffeic acid, adipic acid, and suberic acid, in association with at least one pharmaceutical excipient.