Soluble Salts and Cocrystals of Clotrimazole - Crystal Growth

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Soluble Salts and Cocrystals of Clotrimazole sudhir mittapalli, M. K. Chaitanya Mannava, U. B. Rao Khandavilli, Suryanarayana Allu, and Ashwini Nangia Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.5b00268 • Publication Date (Web): 13 Apr 2015 Downloaded from http://pubs.acs.org on April 14, 2015

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Crystal Growth & Design

Soluble Salts and Cocrystals of Clotrimazole Sudhir Mittapalli,a M. K. Chaitanya Mannava,b U. B. Rao Khandavilli,b Suryanarayana Allu,a and Ashwini Nangia*a, b School of Chemistry,a Technology Business Incubator,b University of Hyderabad, Prof. C. R. Rao Road, Central University PO, Hyderabad 500 046, India. E-mail: [email protected] Abstract Novel crystalline adducts of clotrimazole with pharmaceutically acceptable coformers were prepared. Five salts and two cocrystals of the antimycotic drug clotrimazole (CLT) were crystallized with carboxylic acid conformers adipic acid (ADA), 2,5-dihydroxybenzoic acid (25DHBA), 2,4,6-trihydroxybenzoic acid (246THBA), p-coumaric acid (PCA), caffeic acid (CFA), maleic acid (MA), and suberic acid (SBA). Molecular overlay diagram of clotrimazole in the four salts (CLT–25DHBA, 1:1; CLT–246THBA, 1:1; CLT–PCA, 1:1; CLT–CFA–ANI, 1:1:1) and CLT–ADA (1:0.5) cocrystal showed conformational flexibility of the phenyl rings in the triaryl methane molecule. The X-ray crystal structures are sustained by N+–H···O–/ N–H···O hydrogen bonds. The solid-state forms were well characterized and analyzed by PXRD, FT-IR, and DSC and confirmed by single crystal X-ray diffraction (except for CLT–MA and CLT– SBA adducts). 15N ss-NMR indicated intermolecular proton transfer in CLT–MA and the chemical shifts are consistent with salt formation. The acidic coformers for CLT base were selected based on the ∆pKa rule of 3. Solubility measurements showed improved solubility by a factor of 2.9 (CLT–25DHBA), 14.0 (CLT–246THBA), 1.3 (CLT–PCA), 2.8 (CLT–CFA), 22.4 (CLT–MA) for salts and 5.0 in cocrystals (CLT–ADA and CLT–SBA) compared to CLT in 65% EtOH–water.

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Introduction A majority of active pharmaceuticals ingredients (APIs) in the market show poor physicochemical properties mainly solubility and stability, and this poses serious problems for clinical development and can lead to late stage drug failure.1 Improving the solubility and bioavailability of poorly water soluble drugs is a difficult challenge for pharmaceutical scientists. In addition to salts and cocrystals, other techniques such as micronization, micellar solution, oil encapsulation, and amorphous phase by means of solid dispersions, by using polymers, cyclodextrins and additives have been widely used.2–5 However, salt formation and cocrystallization of the API are the first-choice methods to improve the solubility and bioavailability of poorly soluble drugs using crystal engineering principles6–9 without changing their chemical structure. Salt formation is a preferred method to improve physicochemical properties because it makes the drug molecule ionized and furthermore other favorable factors such as high melting point, crystallinity, filtration, stability, etc. are also optimized in salts.10, 11 Salt formation can improve solubility more than 2000 fold compared to a factor of 50 for cocrystals12, 13 and a mere 5 with polymorphs (these are upper limit numbers). Cocrystal formation is a recent strategy for improving the solubility and stability of nonionizable drugs.14–17 There are multiple techniques to prepare cocrystals such as solution crystallization, solid-state grinding, solvent-assisted grinding, mechanochemical synthesis, etc.18–20 Pharmaceutical cocrystals21, 22 are a subset of the broader cocrystal class wherein a molecular or ionic API and a GRAS coformer (generally regarded as safe by the US-FDA)23 are combined in stoichiometric ratio in a crystalline lattice. The solubility of cocrystal former should typically be 10 times higher than that of the pure API. Remenar et al. reported the first example of a pharmaceutical cocrystal to improve the solubility of anti-fungal drug itraconazole.24 Clotrimazole 1-[(2-chlorophenyl)diphenylmethyl]-1H-imidazole is an imidazole derivative used as an antifungal agent. The drug can also work against different strains of Plasmodium falciparum.25 Malaria has become a global peril due to the spread of resistance to quinolone based antimalarial drugs such as quinine, chloroquine26 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.27 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.28 Efforts to develop new drugs through “repurposing” and “piggy back”29 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 drug30 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.31 Due to its poor and erratic bioavailability, Cmax is reached after 6h 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.32 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 solution33 but it degrades in strongly acidic and basic media and at high temperature. The by-products in strongly acidic medium are (o-chlorophenyl)diphenyl methanol and imidazole34 (Scheme 1).


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Scheme 1 Degradation of Clotrimazole in Acidic Medium. Cl

N

H2

N

H

O/H+

+

OH

∆

N N

Cl

(o-Chlorophenyl)diphenyl methanol

Imidazole

Clotrimazole

The crystal structure of clotrimazole was reported by Song et al. in 1998.35 Prabagar et al. reported β–cyclodextrin inclusion complexes of clotrimazole to increase oral bioavailability. Borhade et al. prepared clotrimazole nanoemulsion to improve drug solubility and dissolution rate.36, 37 There were no reports on salts and cocrystals of clotrimazole to modulate its solubility and stability. Salts and cocrystals of clotrimazole were crystallized using solvent-assistant grinding, melting, and rotary evaporation, neat grinding, etc. We report salts of CLT with 25DHBA, 246THBA, PCA, CFA, MA, and cocrystals with ADA, SBA (Figure 1). The products were characterized by PXRD, IR, DSC, and single crystal XRD (except for MA and SBA adducts). The latter two complexes were characterized by 15N ss-NMR to assign the proton position in the structure. 2 N N1

Cl Clotrimazole (CLT)

COOH

COOH

HO

COOH OH

COOH OH

OH

HO OH

OH

OH

PCA

25DHBA

246THBA

CFA

COOH HOOC

COOH

COOH

HOOC

COOH

ADA

SBA

MA

Figure 1 Molecular structures of the CLT and the list of coformers used in this study. Results and Discussion Clotrimazole (pKa 6.62) is expected to form salts with GRAS organic acids (pKa 2–4) which are not so strong as to degrade clotrimazole. The ∆pKa rule of 339–42 states that salt formation requires at least three units pKa38 difference, whereas ∆pKa of 0.08 Ǻ). Bifurcated C–H···O interactions connect CLT to carbonyl oxygen (O2) (Figure 2b) and dimeric C–H···Cl interactions. Crystallographic data and hydrogen bonds are listed in Table 2 and Table 3.

(a)


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(b) Figure 2 (a) Two molecules of CLT are connected to one molecule of adipic acid by O–H···N synthon. (b) The chains extend via C–H···Cl interactions also we can see the C–H···O interactions. CLT–25DHBA salt (1:1) 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 Ǻ, 169°; Figure 3a). The phenolic hydroxy group ortho to the acid group is involved in intramolecular hydrogen bond (O3–H3A···O1: 1.85 Ǻ, 146°) and the second hydroxy group interacts with O2 (carboxylate) of adjacent 25DHBA‾ (O4–H4A···O2: 1.91 Ǻ, 168°) in a R2 2(14) dimer ring motif43, 44 (Figure 3a). Auxiliary C–H···O (2.46 Ǻ, 152°; 2.56 Ǻ, 139°; Figure 3b) and weak Cl···Cl interactions stabilize the structure (Figure 3c).

(a)

(b)



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(c) Figure 3 (a) Proton transferred from the acid to imidazole nitrogen of CLT and O–H···O hydrogen bond forming R2 2(14) motif. (b) Auxiliary C–H···O interactions. (c) Salt pairs extend through Cl···Cl (type-I) interactions. CLT–246THBA 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: 1.71 Ǻ, 173°; C14–H14···O2: 2.78 Å, 119°) (Figure 4a). The intra molecular hydrogen bonds (O3–H3A···O2: 1.67 Ǻ, 152°; O4–H4A···O1: 1.69 Ǻ, 151°) and the p-hydroxyl donor makes intermolecular hydrogen bond with the carboxylate (O5– H5A···O2: 1.81 Ǻ, 174°) (Figure 4b) to make a wave-like arrangement (Figure 4c). Coformer acid molecules are arranged in a corrugated sheet and CLT molecules hang on alternately through N2–H2A···O1 bond.

(a) (b)


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(c) Figure 4 (a) Proton transfer from coformer acid to CLT. (b) Salt pairs extend through O–H···O bonds. (c) The chains extend in wave with CLT hanging above and below the plane. CLT–PCA Salt (1:1) Single crystals of CLT–PCA 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 Ǻ, 161°; Figure 5a). The acid moieties extend via O1–H1A···O2 (1.90 Ǻ, 174°) and C27–H27···O2 (2.49 Ǻ, 130°) interactions in a 1D tape and further by C10–H10···Cl1 (2.73 Ǻ, 161° ; Figure 5b) interaction at the chlorine atom of CLT.

(a)



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(b) Figure 5 (a) Proton transfer from acid to CLT. (b) The salt pairs extend via C–H···Cl interactions. CLT−CFA–ANI Salt (1:1:1) This salt was prepared by liquid-assisted grinding with acetone by taking equimolar CLT and caffeic acid and the product was characterized by powder XRD, IR. The product was recrystallized from anisole-ethanol, and in this process anisole was included in the crystal lattice (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 Ǻ, 172°). The acid forms two types of tetrameric units, R44(18) and R44 (38) ring motif via O1–H1A···O3 (1.95 Ǻ, 149°), O2–H2C···O4 (1.82 Ǻ, 161°) H bonds and CLT–NH+ ions are arranged alternately above and below the plane of acid tetramers sustained by ionic N2–H2A···O3 bonds (Figure 6a and 6b). 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.

(b)

(a)


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(c) Figure 6 (a) CFA forms a tetramer R44(18) ring motif via O–H···O hydrogen bonds. (b) CFA forms a tetramer R44 (38) ring motif via O–H···O hydrogen bonds. (c) The two tetrameric units are arranged alternately. The included solvent molecules of anisole are not shown for clarity. Conformations of CLT CLT contains three freely rotatable phenyl rings and one imidazole ring connected to a single tertiary carbon atom. CLT exhibits different conformations in its multi-component crystal structures (Figure 7).

Figure 7 Overlay of CLT in salts and cocrystals to show the changes in molecular conformations of phenyl groups. Black: CLT, Red: CLT–ADA, Green: CLT–25DHBA, Magenta: CLT–246THBA, Purple: CLT– PCA, and Blue: CLT–CFA–ANI. Table 2 Crystallographic data of CLT adducts. CLT–ADA cocrystal

CLT–25DHBA salt (1:1)

CLT–246THBA salt (1:1)

CLT–PCA salt (1:1)

(1:0.5) Empirical Formula

C22 H17ClN2.

CLT–CFA–ANI salt solvate (1:1:1)

C22 H18ClN2.

C22 H18ClN2. 9

ACS Paragon Plus Environment

C22 H18ClN2.

C23 H17ClN2. C9


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0.5 (C6 H10O4)

C7H5O4

C7H5O5

C9H7O3

H7O4. C7H8O

Formula weight

417.90

498.94

514.94

508.98

644.12

Crystal system

Triclinic

Triclinic

Monoclinic

Orthorhombic

Monoclinic

Space group

P–1

P–1

P21/n

P212121

P21/c

T (K)

298(2)

298(2)

298(2)

298(2)

100(2)

a (Å)

8.730(9)

10.172(10)

12.0214(14)

10.3536(13)

12.4974(17)

b (Å)

9.654(9)

10.646(8)

13.8128(16)

14.9452(14)

14.527(2)

c (Å)

13.254(13)

13.041(9)

15.9926(18)

16.4976(19)

17.789(2)

α (deg)

74.48(9)

108.469(7)

90.00

90

90.00

Β (deg)

84.281(8)

102.963(8)

97.934(2)

90

96.028(2)

γ (deg)

85.466(8)

107.069(8)

90.00

90

90.00

V (Å3)

1069.4(18)

1200.12(17)

2630.1(5)

2552.8(5)

3211.7(7)

Dcalcd (gcm–3)

1.298

1.381

1.300

1.324

1.332

µ (mm–1)

0.203

0.199

0.187

0.186

0.168

θ range

2.73 to 26.37

2.94 to 26.37

1.96 to 28.3

2.69 to 26.37

1.64 to 25.00

Z/Z1

2/1

2/1

4/1

4/1

4/1

Range h

–6 to 10

–12 to 12

–15 to 16

–12 to 12

–14 to 14

Range k

–12 to 12

–13 to 13

–18 to 18

–11 to 18

–17 to 17

Range l

–16 to 16

–15 to 16

–21 to 21

–20 to 12

–21 to 21

Reflections collected

7803

8431

30171

7083

30355

Total reflections

4368

4889

6337

4539

5662

Observed reflections

3471

3471

3515

1495

4791

R1 [I > 2 σ (I) ]

0.058

0.050

0.082

0.074

0.075

wR2 (all)

0.083

0.125

0.161

0.125

0.237

Goodness-of-fit

0.776

1.031

1.097

0.829

1.087

X-Ray Diffractometer

Oxford Xcalibur

Oxford Xcalibur

Bruker Smart

Oxford Xcalibur

Bruker Smart

Table 3 Hydrogen bond geometry in CLT crystal structures (neutron-normalized).


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1 2 3 Cocrystal/Salt Interaction D–H/Å H···A/Å D···A/Å Symmetry ∠D–H···A/Å 4 code 5 6 CLT–ADA O1–H1A···N2 0.82 1.84 2.654(4) 174 –1+x,y,z 7 8 (1:0.5) C21–H21···O2 0.93 2.45 3.377(4) 172 1+x,1+y,z 9 10 N2–H2A···O1 0.86 1.80 2.65(3) 169 –x,1–y,–z 11 O3–H3A ···O1 0.82 1.85 2.570(3) 146 Intramolecular 12 13 O4–H4A···O2 0.82 1.91 2.714(3) 168 –x,1–y,–z 14CLT–25DHBA 15 (1:1) C14–H14···O3 0.93 2.56 3.318(3) 139 x,–1+y,z 16 17 C15–H15···O2 0.93 2.46 3.309(3) 152 1+x,y,z 18 19 N2–H2A···O1 0.93 1.71 2.651(3) 173 1+x,y,z 20 O3–H3A···O2 0.96 1.67 2.553(3) 152 Intramolecular 21 22 O4–H4A···O1 0.87 1.69 2.526(4) 151 Intramolecular 23 24 O5–H5A···O2 0.88 1.81 2.683(3) 174 1/2– 25 x,1/2+y,1/2–z 26CLT–246THBA 27 C12–H12 ···O4 0.93 2.57 3.375(4) 145 1/2+x,1/2–y,– (1:1) 28 1/2+z 29 30 C8–H8···O5 0.93 2.58 3.350(4) 141 3/2–x,– 31 1/2+y,1/2–z 32 33 C15–H15···O3 0.93 2.50 3.276(3) 141 1/2+x,1/2– 34 y,1/2+z 35 36 O1–H1A···O2 0.82 1.90 2.713(8) 174 –1+x,y,z 37 38 N2–H2A···O3 0.86 1.78 2.608(8) 161 2–x,– 39 1/2+y,1/2–z 40CLT–PCA (1:1) 41 C27–H27···O2 0.93 2.49 3.170(10) 130 –1+x,y,z 42 43 C10–H10···Cl1 0.93 2.73 3.624(8) 161 1/2+x,1/2–y,z 44 45 O1–H1A···O3 0.82 1.95 2.689(3) 149 x,3/2–y,– 46 1/2+z 47CLT–CFA–ANI 48 N2–H2A···O3 0.86 1.81 2.661(3) 172 x,3/2–y,– (1:1:1) 49 1/2+z 50 51 O2–H2C···O4 0.82 1.82 2.611(3) 161 –x,– 52 1/2+y,1/2–z 53 54 Powder X-ray Diffraction 55 56 Overlay of the experimental powder XRD pattern on the calculated lines for the crystal structure confirms 57 purity and homogeneity of the bulk phase for CLT–ADA, CLT–25DHBA, CLT–246THBA, CLT–PCA 58 59 11 60 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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(Figure 8). CLT–CFA salt was crystallized from anisole–EtOH solvent mixture and it included anisole in the crystal lattice to give CLT–CFA–ANI (1:1:1). The powder diffraction pattern of the ground products and the starting materials are shown in Figure S17 (Supporting information). 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 (Figure S1 and Figure S2, Supporting Information) suggests the formation of a novel solid form, which is supported by DSC (Figure 9) and TGA (Figure S18–S19, Supporting information). 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 CLT. In the case of adipic acid and suberic acid adducts (neutral cocrystals), the C=O stretching frequencies observed at 1694.5, 1700.0 cm-1 (no proton transfer and COOH group peak is similar to the pure coformer), whereas when the COOH proton is transferred to the imidazolium nitrogen of CLT, the COO– (asym stretch) frequency is red shifted and the N–H (stretch) frequency is present (Table 4 and Figure S3–S9, Supporting Information).

Table 4 Stretching and Bending Frequencies of CLT adducts. Compound

C=N

N–H

Carboxylate/

(cm-1)

(cm-1)

carboxylic acid (asym) (cm-1)

Carboxylate (sym) (cm-1)

Carboxylic acid (coformer) C=O stretch (cm-1)

CLT

1646.7

--

--

--

--

CLT–ADA

1567.2

--

1694.5

--

1693.1

CLT–25DHBA

1618.3

3426.2

1567.9

1381.3

1669.6

CLT–246THBA

1634.7

3449.3

1603.0

1420.9

1663.3

CLT–PCA

1604.3

3453.4

1587.1

1374.2

1672.3

CLT–CFA

1640.4

3437.6

1585.7

1379.1

1646.0

CLT–MA

1584.4

3483.1

1701.8, 1622.0

1443.2

1706.8

CLT–SBA

1640

--

1700.0

--

1702.8


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Figure 8 Overlay of experimental PXRD patterns of novel crystal forms of CLT on the calculated lines from the X-ray crystal structure. Solid-state NMR 15

N CP–MAS is the best tool to identify salt formation or inter/intra molecular proton transfer.45, 46 Clotrimazole consists of two nitrogen atoms (N1, N2) and their chemical shifts were observed at 186 and 262 ppm. Transfer of the proton from the carboxylic acid to the N2 of CLT increases shielding of the nitrogen to result in an upfield chemical shift. Salts showed significant decrease in the 15N chemical shift values (shielding) compared to pure clotrimazole (most deshielded N2) indicating salt formation (Figure S10, Supporting Information) whereas there is not much change observed in ADA and SBA cocrystals (Table 5). The 1:0.5 stoichiometry of CLT–MA salt and CLT–SBA cocrystal was confirmed by 1H NMR proton integration (Figure S11 and S12, Supporting Information). Table 5 15N ss-NMR chemical shift values (δ, ppm).a Compound name

Chemical shift of N1 , N2 (ppm)

CLT

186, 262

CLT–ADA (1:0.5)

184, 242



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a

CLT–SBA (1:0.5)

183, 239

CLT–25DHBA (1:1)

189.2, 191

CLT–246THBA (1:1)

175, 190

CLT–MA (1:0.5)

184, 193

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N2 is hydrogen bonded to the COOH group and N1 is the internal imidazole nitrogen.

Thermal Analysis 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, 246THBA, PCA, CFA, MA, and SBA cocrystal are 154.5 °C, 150 °C, 170.3 °C, 141.1 °C, 122 °C, and 130 °C. CLT–PCA exhibited the highest melting point (170.3 °C) and CLT–MA has the lowest melting point (122 °C). DSC thermograms are displayed in Figure 9, and of CLT–246THBA in Figure S13 (Supporting Information), and melting points are listed in Table 6.

Figure 9 DSC thermograms of CLT salts/cocrystal. Table 6 Melting points of CLT cocrystals and salts from DSC. S.No

Compound

Melting point of API/Coformer (°C)

1

CLT

148

--

2

CLT–ADA (1:0.5)

152

134.9

3

CLT–25DHBA (1:1)

203

154.5

4

CLT–246THBA (1:1)

210

150.0

5

CLT–PCA (1:1)

211

170.3


Melting Point of cocrystal/salt (°C)

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Solubility and Dissolution studies


6

CLT–CFA (1:1)

223

141.1

7

CLT–MA (1:0.5)

135

122.0

8

CLT–SBA (1:0.5)

142

130.0

Poor solubility is the major issue in the pharmaceutical industry for many drugs because poor pharmacokinetic and pharmacodynamic properties limit bioavailability. Improvement in dissolution rate and solubility by means of supramolecular modification of an API is a crystal engineering strategy. Solubility experiments of CLT (a BCS Class II drug) and its cocrystals/salts (CLT–ADA, CLT–25DHBA, CLT–246THBA, CLT–PCA, CLT–CFA, CLT–MA, CLT–SBA) were performed in 65% EtOH–H2O medium due to poor aqueous solubility of CLT (0.49 µg/mL). The solubility of CLT in 65% EtOH–H2O after 24 hrs is 4.4 mg/L. Equilibrium Solubility experiments for salts were performed for 24 h (the salts were stable for more than 24h as confirmed by PXRD, Figure S14–16, Supporting Information). Normally solubility and dissolution is measured by plotting a calibration curve for the chromophore in the drug molecule using UV-Vis spectroscopy. For CLT–25DHBA, CLT–246THBA, CLT–PCA, and CLT–CFA the coformer absorption interferes with that of CLT (at 262 nm) due to the aromatic ring in the conformer acid. Hence the solubility of these salts was determined by analytical HPLC (Table 7) using acetonitrile and 1% acetic acid as the mobile phase (1:1 v/v). 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 4h 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 (Figure 10). The dissolution rate of CLT–MA, CLT–SBA adducts were 1.7 times higher than CLT, while CLT–ADA cocrystal decreased by 2.6 times. The area under the curve AUC0–4h for CLT–MA is high at 1234 mg h/L due to high equilibrium solubility (measured at 24h) and high solution concentration of the drug (measured at 240 min). Dissolution and AUC measurements on CLT salts with aromatic carboxylic acids are pending because it is a tedious task to record the 12 or so readings over 240 min using HPLC (and also making calibration curves). The overlapping peaks from the chromophore of the drug and the coformer make difficult a rapid UV-Vis analysis of CLT concentration.



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Figure 10 Intrinsic dissolution rate of CLT and its cocrystals and salts in 65% EtOH–H2O.

Table 7 Intrinsic dissolution rate and solubilitya of CLT cocrystals/salts. Compound

Aqueous Solubility of API/Coformer

Molar extinction coefficient,

Equilibrium Solubility mg/L

Solution concentration in mg/mL (240 min)

Area under the curve, AUC 0–4h (mg h)/L

mg/mL

ε /mM cm

CLT

0.00049

1.609

4.40

0.972

427

CLT–ADA

23

0.750

22.06 (×5.0)

0.370 (×0.38)

234.58

CLT–MA

780

1.000

98.79 (×22.43)

1.740 (×1.79)

1233.82

CLT–SBA

11.9

0.563

22.01 (×4.99)

1.658 (×1.70)

867.23

CLT–25DHBA

5

--

13.11 (×2.97)

--

--

CLT–246THBA

18.6b

--

61.87 (×14.04)

--

--

CLT–PCA

18.3b

--

5.84 (×1.32)

--

--

CLT–CFA

54b

--

12.48 (×2.83)

--

--

a

Equilibrium solubility was measured for all samples using HPLC method. Dissolution curve requires multiple measurements, and this value was determined for the aliphatic carboxylic acid coformers only


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where there is no interference for the UV-Vis maximum peak of CLT with those for the conformers, i.e. the aromatic carboxylic acids were excluded from dissolution measurements. b

Aqueous solubility of compounds is taken from http://www.chemspider.com/ . Conclusions

We have prepared seven novel solid forms of CLT by using the ∆pKa Rule of 3, CLT–ADA, CLT–SBA cocrystals and CLT–25DHBA, CLT–246THBA, CLT–PCA, CLT–CFA, CLT–MA salts. In salts structures, the carboxylic acid proton is transferred to the imidazole nitrogen (N2) of the CLT through ionic N+–H···O− hydrogen bond except in CLT–ADA cocrystal which is sustained by neutral COOH···N hydrogen bond. Solubility experiments were performed in 65% EtOH–water for CLT–25DHBA, CLT– 246THBA, CLT–PCA, CLT–CFA, CLT–MA salts and CLT–ADA, CLT–SBA cocrystals. The solubility of CLT–MA salt is 22 times higher compared to CLT and net drug dissolved in 4h (the early dissolution phase for any drug) is 1.79 times. These preliminary studies encourage us to explore a soluble salt of clotrimazole for anti-malarial therapy47 in the future.

Experimental Section Clotrimazole was purchased from Yarrow chemicals, Mumbai, India. Solvents (purity > 99%), other coformers were purchased from Hychem Laboratories (Hyderabad, India) and Sigma–Aldrich (Hyderabad, India). Water filtered through a double deionizer purification system (Aqua DM, Bhanu, Hyderabad, India) was used for all experiments. 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, 0.5 mol) in a mortar and pestle for 15 min using acetone as solvent. The formed salt was characterized by PXRD, IR and DSC. Colorless single crystals suitable for single crystal XRD are developed by upon dissolving the material in ethanol– CHCl3 (1:1) solvent mixture left for solvent evaporation at ambient conditions for 3–4 days. m.p. 134.9 °C. CLT–25DHBA 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 25DHBA (154.12 mg, 1 mol) in a mortar and pestle for 15 min using acetone as solvent. The formed salt was characterized by PXRD, IR and DSC. Colorless single crystals suitable for single crystal XRD are developed by upon dissolving the material in ethanol– CHCl3 (1:1) solvent mixture and left for solvent evaporation. m.p. 154.5 °C. CLT–246THBA Salt (1:1) Clotrimazole and 2,4,6-tri hydroxybenzoic acid were ground in 1:1 stoichiometric ratio of CLT (344.83 mg, 1mol) and 246THBA (170.12 mg, 1mol) in a mortar and pestle for 15 min using acetone as solvent. The formed salt was characterized by PXRD, IR and DSC. Colorless single crystals suitable for single crystal XRD are developed by upon dissolving the material in ethanol– anisole (1:1) solvent mixture left for solvent evaporation. m.p. 150 °C. 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. The formed salt was characterized by PXRD, IR and DSC. Colorless single crystals suitable for single crystal XRD are developed by upon dissolving the material in ethanol–anisole (1:1) solvent mixture left for solvent evaporation. m.p. 170 °C.



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CLT–CFA (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. The formed salt was characterized by PXRD, IR and DSC. Colorless single crystals suitable for single crystal XRD are developed by upon dissolving the material in ethanol–anisole (1:1) solvent mixture left for solvent evaporation. m.p. 141 °C. 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, 0.5 mol) in a mortar and pestle for 15 min using acetone as solvent. The formed salt was characterized by PXRD, IR and DSC. m.p. 122 °C. 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, 1mol) and SBA (87.1 mg, 0.5 mol) in a mortar and pestle for 15 min using acetone as solvent. The formed salt was characterized by PXRD, IR and DSC. m.p. 130 °C. The coformers used to crystallize binary systems but did not result in any phase change are displayed in Table S1, Supporting Information. X–ray Crystallography 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-Kα radiation (λ = 0.7107 Å). Data reduction was performed using CrysAlisPro (version 1.171.33.55)48 and OLEX249 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-Kα fine-focus sealed tube (λ = 0.71073 Å). Data reduction was performed using Bruker SAINTSoftware.50 Intensities were corrected for absorption using SADABS,51 and the structure was solved and refined using SHELX-97.52, 53 All nonhydrogen 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.54 X-Seed55 was used to prepare packing diagrams. Crystal structures are deposited as part of the Supporting Information and may be accessed at www.ccdc.cam.ac.uk/data_request/cif (CCDC Nos. 1050767–1050771). Powder X-ray Diffraction Powder X-ray diffraction was recorded on Bruker D8 Advance diffractometer (Bruker-AXS, Karlsruhe, Germany) using Cu-Kα X-radiation (λ = 1.5406 Å) at 40 kV and 30 mA power. X-ray diffraction patterns were collected over the 2θ range 5–50° at a scan rate of 1°/min. Vibrational Spectroscopy Nicolet 6700 FT–IR spectrometer with a NXR FT–Raman Module was used to record IR spectra. IR spectra were recorded on samples dispersed in KBr pellets. Solid–State NMR Spectroscopy Solid-state 15N–NMR spectra were recorded on Bruker Avance 400 MHz spectrometer (Bruker–Biospin, Karlsruhe, Germany). ss-NMR measurements were carried out on Bruker 4-mm double resonance N15CP– MAS probe in zirconia rotors with a Kel-F cap at 5.0 kHz spinning rate with a cross-polarization contact time of 4 ms and a delay of 8 s. 15N–NMR spectra were recorded at 40 MHz and referenced to the glycine N, and then chemical shifts are recalibrated to nitromethane (δglycine = –347.6 ppm).


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Thermal Analysis DSC was performed on a Mettler Toledo DSC 822e module. Samples were placed in crimped but vented aluminum sample pans. The typical sample size is 4–6 mg, temperature range was 30–250 °C @ 5 °C/min. Samples were purged by a stream of nitrogen flowing at 150 mL/min. Dissolution and Solubility Measurements The solubility curves of CLT salts and cocrystal were measured using the Higuchi and Connor method in 65% ethanol–water medium at 37 °C. First, the absorbance of a known concentration of the salt was measured at the given λmax (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 24h, 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 λmax. 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. Supporting Information Crystallographic information files: CCDC Nos. 1050767–1050771; Figure S1–S9: IR comparison of new solid phases with their starting materials; Figure S10: Solid-state 15N NMR chemical shift (ppm) values of CLT salts and cocrystals; Figure S11: 1H NMR of CLT–MA salt shows 1:0.5 stoichiometric ratios of the components; Figure S12: 1H NMR of CLT–SBA cocrystal shows 1:0.5 stoichiometric ratios of the components; Figure S13: DSC thermogram of CLT–246THBA salt; Figure S14–S16: Comparison of powder XRD pattern of salts and cocrystals with the calculated line pattern from the X-ray crystal structure shows stability of these adducts in the solubility medium (65% EtOH–Water) for 1 day; Figure S17: PXRD Comparison for the CLT–CFA salt with its starting materials; Figure S18: TGA analysis for CLT– MA salt. Figure S19; TGA analysis for CLT–SBA cocrystal; Table S1: pKa values for coformers used in this study. This material is available free of charge via the Internet at http://pubs.acs.org. Corresponding authors *E mail: [email protected] Notes The authors declare no competing financial interest. Acknowledgments This research was funded by JC Bose fellowship SR/S2/JCB–06/2009 and SERB scheme SR/S1/OC–37/2011. DST–IRPHA and UGC–PURSE are thanked for providing instrumentation 19 ACS Paragon Plus Environment


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and infrastructure facilities. SM and SA thank UGC and University of Hyderabad for fellowship. MKCM and UBRK thank Crystalin Research, Hyderabad for support. References 1. Kola, I.; Landis, J. Can The Pharmaceutical Industry Reduce Attrition Rates? Nat. Rev. Drug Discovery 2004, 3, 711–715. 2. Chaumeil, J. C. Methods Find Exp. Clin. Pharmacol. 1998, 20, 211–215. 3. Rajput, L.; Sanphui, P.; Desiraju G. R. Cryst. Growth Des. 2013, 13, 3681–3690. 4. Torchillin, V. P. Pharm. Res. 2007, 24, 1. 5. Rajewski, R. A.; Stella, V. J. J. Pharm. Sci. 1996, 85, 1142–1169. 6. Huang, L. F.; Tong, W. Q. Adv. Drug Delivery Rev. 2004, 56, 321–334. 7. Karki, S.; Friscic, T.; Fabian, L.; Laity, P. R.; Day, G. M.; Jones, W. Adv. Mater. 2009, 21, 3905– 3909. 8. Babu, N. J.; Sanphui, P.; Nangia. A. Chem. Asian. J. 2012, 7, 2274–2285. 9. Blagden, N.; Matas, M. D.; Gavan, P. T.; York. P. Adv. Drug Delivery Rev. 2007, 59, 617–630. 10. Thakuria, R.; Nangia, A. CrystEngComm 2011, 13, 1759–1764. 11. Berge, S. M.; Bighley, L. D.; Monkhouse, D. C. J. Pharm. Sci. 1977, 66, 1–19. 12. Sanphui, P.; Bolla, G.; Nangia, A. Cryst. Growth Des. 2012, 12, 2023–2036. 13. Elder, D. P.; Holm, R.; Heidi Lopez de Diego. Int. J. Pharm. 2013, 453, 88–100. 14. Brittain, H. G. Cryst. Growth Des. 2012, 12, 5823–5832. 15. Babu, N. J.; Nangia, A. Cryst. Growth Des. 2011, 11, 2662–2679. 16. Thakuria, R.; Delori, A.; Jones, W.; Lipert, M. P.; Roy, L.; Rodríguez-Hornedo, N. Int. J. Pharm. 2013, 453, 101–125. 17. Datta, S.; Grant, D. J. W. Nat. Rev. Drug Discovery, 2004, 3, 42–57. 18. Etter, M. C.; Frankenbach, G. M.; Chem. Mater. 1989, 1, 10–12. 19. Scheffer, J. R.; Wong, Y. F.; Patil, A. O.; Curtin, D. Y.; Paul, I. C. J. Am. Chem. Soc. 1985, 107, 4898–4904. 20. Trask, A. V.; Motherwell, W. D. S.; Jones, W. Chem. Commun. 2004, 890–891. 21. Almarsson, O.; Zaworotko, M. J. Chem. Commun. 2004, 1889–1896. 22. Sanphui, P.; Kumar, S. S.; Nangia, A. Cryst. Growth Des. 2012, 12, 4588–4599. 23. Generally

Regarded

as

Safe

chemicals

by

the

U.S.

FDA.

http://www.fda.gov/Food/IngredientsPackagingLabeling/FoodAdditivesIngredients/ucm091048.htm (Accessed 14 Feb. 2015).


Page 21 of 23

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


24. Remenar, J. F.; Morissette, S. L.; Peterson, M. L.; Moulton, B.; MacPhee, J. M.; Guzman, H. R.; Almarsson, O. J. Am. Chem. Soc. 2003, 125, 8456–8457. 25. Saliba, K. J.; Kirk, K. Trans. R. Soc. Trop. Med. Hyg. 1998, 92, 666–667. 26. Trigg, P. I.; Kondrachine, A.V. Malaria: Parasite Biology, Pathogenesis, and Protection, Sherman, I. W.; Ed, 11–22, ASM Press, Washington, D. C., 1998. 27. World

Malaria

Report,

2010,

http://www.who.int/malaria/world_malaria_report_2010/worldmalariareport2010.pdf, (Accessed 14 Feb. 2015). 28. Bangchang, K. N.; Karbwang, J. Fundamental and Clinical Pharmacology 2009, 23, 387–409. 29. Gelb, M. H. Curr. Opin. Chem. Biol. 2007, 11, 440–445. 30. Mehta, M.; Panchal, A.; Shah, V. H.; Upadhyay, U. Int. J. Adv. Pharm. 2012, 2, 93–101. 31. Huy, N. T.; Kamei, K.; Yamamoto, T.; Kondo, Y.; Kanaori, K.; Takano, R.; Tajima, K.; Hara, S. J Biol Chem. 2002, 277, 4152–4158. 32. Tiffert, T.; Ginsburg, H.; Krugliak, M.; Elford, B. C.; Lew, V. L. Proc. Natl. Acad. Sci. 2000, 97, 331– 336. 33. Borhade, V.; Pathak, S.; Sharma, S.; Patravale, V. Int. J. Pharm. 2012, 431, 138–148. 34. Abdel-Moety, E. M.; Khattab, F. I.; Kelani, K. M.; AbouAl-Alamein, A. M. II Farmaco 2002, 57, 931–938. 35. Song, H.; Shin, H. S. Acta Crystallogr. Sect. C 1998, 54, 1675–1677. 36. Prabagar, B.; Yoo, B. K.; Woo, J. S.; Kim, J. A.; Rhee, J. D.; Piao, M. G.; Choi, H. G.; Yong, C. S. Arch. Pharm. Res. 2007, 30, 249–254. 37. Borhade, V.; Pathak, S.; Sharma, S.; Patravale, V. Int. J. Pharm. 2012, 431, 149–160. 38. Marvin 5.10.1, 2012, ChemAxon, http://www.chemaxon.com (Accessed 14 Feb. 2015). 39. Aakeroy, C. B.; Fasulo, M. E.; Desper, J. Mol. Pharmaceutics 2007, 4, 317–322. 40. Sarma, B.; Nath, N. K.; Bhogala, B. R.; Nangia, A. Cryst. Growth Des. 2009, 9, 1546–1557. 41. Childs, S. L.; Stahly, G. P.; Park, A. Mol. Pharmaceutics 2007, 4, 323–338. 42. Cruz-Cabeza, A. J. CrystEngComm 2012, 14, 6362–6365. 43. Etter, M. C. Acc. Chem. Res. 1990, 23, 120–126. 44. Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N. L. Angew. Chem., Int. Ed. Engl. 1995, 34, 1555– 1573. 45. Gobetto, R.; Nervi, C.; Chierotti, M. R.; Braga, D.; Maini, L.; Grepioni, F.; Harris, R. K.; Hodgkinson, P. Chem. Eur. J. 2005, 11, 7461–747. 46. Martin, F. A.; Pop, M. M.; Borodi, G.; Filip, X.; Kacso, I. Cryst.Growth Des. 2013, 13, 4295–4304. 47. Kumar, S.; Guha, M.; Choubey, V.; Maity, P.; Bandyopadhyay, U. Life Sciences 2007, 80, 813–828. 21 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 23

48. Crysalis CCD and Crysalis RED, ver. 1.171.33.55; Oxford Diffraction Ltd., Yarnton, Oxfordshire, UK, 2008. 49. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. OLEX2: A complete structure solution, refinement and analysis program. J. Appl. Crystallogr. 2009, 42, 339–341. 50. SAINT-Plus, version 6.45; Bruker AXS Inc.: Madison, Wisconsin, U.S.A., 2003. 51. SADABS, Program for Empirical Absorption Correction of Area Detector Data; Sheldrick, G. M. University of Gottingen: Gottingen, Germany, 1997. 52. SMART, version 5.625 and SHELX-TL, version 6.12; Bruker AXS Inc.: Madison, Wisconsin, USA, 2000. 53. Sheldrick, G. M. SHELXS-97 and SHELXL-97; University of Gottingen: Gottingen, Germany, 1997. 54. Spek, A. L. PLATON, A Multipurpose Crystallographic Tool; Utrecht University: Utrecht, Netherlands, 2002. 55. 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.


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Table of Contents

Soluble Salts and Cocrystals of Clotrimazole Sudhir Mittapalli,a M. K. Chaitanya Mannava,b U. B. Rao Khandavilli,b Suryanarayana Allu,a and Ashwini Nangia*a, b School of Chemistry,a Technology Business Incubator,b University of Hyderabad, Prof. C. R. Rao Road, Central University PO, Hyderabad 500 046, India. Table of Content Graphic

Synopsis Novel crystalline forms of Clotrimazole with GRAS coformers showed improved solubility compared to the pure drug in the order CLT–MA > CLT–246THBA > CLT–ADA = CLT–SBA > CLT–25DHBA = CLT–CFA > CLT–PCA > and CLT.


Soluble Salts and Cocrystals of Clotrimazole - Crystal Growth

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