Article pubs.acs.org/crystal
Stable Crystalline Salts of Haloperidol: A Highly Water-Soluble Mesylate Salt Lalit Rajput* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India S Supporting Information *
ABSTRACT: Haloperidol, an antipsychotic drug, was screened for new solid crystalline phases using high throughput crystallization in pursuit of solubility improvement. Due to the highly basic nature of the API, all the solid forms with acids were obtained in the form of salts. Eleven crystalline salts in the form of oxalate (1:1), benzoate (1:1), salicylate (1:1 and 1:2), 4hydroxybenzoate (1:1), 4-hydroxybenzoate ethyl acetate solvate (1:1:1), 3,4dihydroxybenzoate (1:1), 3,5-dihydroxybenzoate (1:1), mesylate (1:1), besylate (1:1), and tosylate (1:1) salt were achieved. There is an insertion of carboxylate or sulfonate anion into the hydrogen bonding pattern of haloperidol. The salts with the aliphatic carboxylic acids were found to be more prone to form salt hydrates compared with aromatic carboxylate salts. All the salts were subjected to solubility measurement in water at neutral pH. There was no direct correlation observed between the solubility of the salt and its coformer. All the salts are stable at room temperature as well as after 24 h slurry experiment except the oxalate salt, which showed an unusual phase transformation from its hydrated form to the anhydrous form. A structure−property relationship was examined to analyze the solubility behavior of the solid forms.
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INTRODUCTION Crystal engineering has provided a new and efficient approach for the tuning of the physicochemical properties of active pharmaceutical ingredients (API), and this in turn has a direct application in the pharmaceutical industry.1 APIs can exist in the form of polymorphs, salts, cocrystals, hydrates, or solvates and may exhibit distinct physical properties compared with the parent API.2 Among these, salt or cocrystal formation is nowadays commonly put into practice in the pharmaceutical industry where the API is crystallized with a generally regarded as safe (GRAS) coformer.3 The coformer can modulate the stability, solubility, bioavailability, and tableting attributes of the API.4 Currently almost 40% of marketed drugs face the major problem of poor aqueous solubility, which affects the absorption in the GI track.5 Solubility of an API is related to issues such as bioavailability and permeability. Several methods such as making an amorphous phase by using polymer, solid dispersion, additives, excipients, and cyclodextrin can be implemented to improve the solubility of an API.6 However, salt or cocrystal formation still remains as one of the best approaches for solubility improvement without disturbing the inherent pharmacological properties of the API. To design cocrystals or salts, a crystal engineering approach based on supramolecular synthons is advantageous.7 Cocrystal formation can improve the solubility by 100 times, whereas salts can modulate the solubility almost 1000-fold.8 Salt formation is the most common method for improving solubility and today more than 50% of APIs are marketed as salts.9 However, salt formation is limited to ionizable APIs exhibiting acidic or basic © XXXX American Chemical Society
functional sites. The formation of salt or cocrystal can be predicted by the ΔpKa rule (ΔpKa = pKa(base) − pKa(acid)).10 It is assumed that if the ΔpKa < 0, a cocrystal will be formed while if ΔpKa > 3 salt formation will ensure. In the intermediate range of 0 < ΔpKa < 3, there is a possibility of formation of salt, cocrystal, or salt−cocrystal continuum. This “rule of three” is helpful to predict the outcome of a particular combination of API and coformer. However, several groups have found that this ΔpKa range can extend for particular systems, and the maximum until now reported is −1 to 4.11 In continuation of our efforts to improve the physiochemical properties of APIs with a crystal engineering approach, we have selected an antipsychotic drug, haloperidol (HAL).12 Haloperidol, 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4-fluorophenyl)-butan-1-one, is a butyrophenone derivative and functions as an inverse agonist of dopamine in the biological system.13 Generally it is prescribed for the treatment of schizophrenia. It is on the list of World Health Organization essential medicines for basic health care.14 Haloperidol (trade name Haldol) is a BCS class II drug and exhibits low solubility (14 mg/L) and high permeability (log P = 4.3).15 It is almost insoluble in water over a wide range of pH and is stable at room temperature. The flexible molecule has a central cyclohexane ring with tertiary amine nitrogen, an alcoholic hydroxy, and ketone functionality (Scheme 1). In the crystal structure of Received: July 2, 2014 Revised: August 18, 2014
A
dx.doi.org/10.1021/cg500982u | Cryst. Growth Des. XXXX, XXX, XXX−XXX
Crystal Growth & Design
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Scheme 1. Schematic Representation of Haloperidol and the Coformers Used in the Study
Table 1. Calculated ΔpKa between Haloperidol and the Acid Coformer compound
OA
BA
SA
4HBA
34DHBA
35DHBA
MES
BES
TOS
pKa ΔpKa = pKa(HAL) − pKa(acid)
1.23 7.07
4.19 4.11
2.98 5.32
4.54 3.76
4.48 3.82
4.04 4.26
−1.9 10.2
0.70 7.60
−2.8 11.10
haloperidol, the molecules are assembled through strong O− H···N hydrogen bonds between the tertiary amine nitrogen and hydroxy functionality.16 Previously our group has studied the crystal structure and solubility of saccharinate salt of haloperidol.17 The crystal structures of the hydrochloride, hydrobromide, and picrate salts of haloperidol are also documented in the literature.18 During the preparation of this manuscript, Aitipamula et al. have reported some aliphatic salts of haloperidol and a polymorph of the saccharinate salt.19 An extensive solubility study has been attempted on the mesylate salt of haloperidol at different pH as well as in the presence of surfactants.20 However, until now there is no report on the crystal structure of the mesylate salt. It has been noted that the kinetics plays an important role for dissolution of the mesylate and phosphate salts of haloperidol before they get converted to the poorly soluble hydrochloride salt in the system.21 Therefore, it is worthwhile to attempt new solid forms of haloperidol in pursuit of solubility improvement. In this regard, the structure−property relationship studies can be helpful to understand the properties of the multicomponent molecular crystals.22 The molecular arrangement can have a better justification for the physical properties of crystalline solids, which can be tuned by altering the intermolecular interactions, especially hydrogen bonds. In this report, we discuss our efforts to improve the solubility of haloperidol by preparing its crystalline salts for the development of new dosage forms and studying their structural aspects to correlate the structure−property relationships. The
new solid forms were characterized by FT-IR, DSC, powder, and single crystal X-ray diffraction.
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RESULTS AND DISCUSSION Haloperidol was screened for new solid phases using high throughput crystallization. It is observed that the strong basic character of the API (pKa = 8.30) makes it prone to form salts even with weak acids. The ΔpKa is calculated for all the combinations (Table 1), and we observed that it is greater than 3 indicating the possibility of salt formation in each new solid form. Eleven new salts with oxalic acid (1:1; 1), benzoic acid (1:1; 2), salicylic acid (1:2; 3A), salicylic acid (1:1; 3B), 4hydroxybenzoic acid (1:1; 4), 4-hydroxybenzoic acid and ethyl acetate (1:1:1; 4-EA), 3,4-dihydroxybenzoic acid (1:1; 5), 3,5dihydroxybenzoic acid (1:1; 6), methanesulfonic acid (1:1; 7), benzenesulfonic acid (1:1; 8), and p-toluenesulfonic acid (1:1; 9) were obtained from various solvents and solvent combinations. In all cases, the tertiary amine nitrogen atom is protonated. The crystallographic parameters and solubility results are summarized in Tables 2 and 3, respectively. We now discuss the structural aspects of the salts. Oxalate Salt Trihydrate (1). The salt crystallizes in the triclinic crystal system with the P1̅ space group (Z = 2). The asymmetric unit contains one protonated haloperidol, half unit each of oxalate anion and oxalic acid, and three water molecules. Haloperidol adopts a linear geometry, and the two protonated haloperidol molecules are held together by an oxalate anion with bifurcated N(+)−H···O(−) hydrogen bonds (Figure 1a). The oxalate anion and acid unit is interacting via B
dx.doi.org/10.1021/cg500982u | Cryst. Growth Des. XXXX, XXX, XXX−XXX
Crystal Growth & Design
Article
Table 2. Crystallographic Parameters of Compounds 1−9 compound emp formula formula wt cryst syst space group T (K) a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) vol (Å3) Dcalcd (g cm−3) Z 2θ range R1 (I > 2σ(I)), wR2 GOF compound emp formula formula wt cryst syst space group T (K) a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) vol (Å3) Dcalcd (g cm−3) Z 2θ range R1 (I > 2σ(I)), wR2 GOF
1 C23H28NO9FCl 516.91 Triclinic P1̅ 150 10.9398(17) 11.0705(17) 11.7353(18) 106.846(7) 100.623(7) 102.977(7) 1277.2(4) 1.344 2 3.0 to 27.6 0.0985, 0.2414 1.153 5 C28H29NO6FCl 529.97 monoclinic Cc 150 18.369(2) 13.1210(13) 12.0966(17) 90 119.324(4) 90 2541.9(5) 1.385 4 2.3 to 27.5 0.0569, 0.1688 1.017
2 C28H29NO4FCl 497.97 Orthorhombic P212121 150 6.002(3) 11.525(7) 35.29(2) 90 90 90 2441(2) 1.355 4 2.1 to 27.5 0.0475, 0.1549 1.120 6 C28 H29NO4FCl 529.97 monoclinic P21/c 150 8.2696(11) 14.4385(16) 21.086(3) 90 101.095(4) 90 2470.6(6) 1.425 4 1.8 to 27.5 0.0621, 0.1853 1.075
3A C35H35NO8FCl 652.09 Monoclinic Cc 150 36.09(2) 8.178(4) 11.344(6) 90 107.542(11) 90 3192(3) 1.357 4 2.4 to 27.5 0.0457, 0.1423 1.310 7 C22H29NO7SFCl 505.98 triclinic P1̅ 150 9.5485(12) 10.3924(13) 13.2217(16) 107.554(8) 98.463(7) 104.392(7) 1176.1(3) 1.429 2 3.1 to 27.6 0.0528, 0.1630 1.074
coformer solubility (g/L)
residue obtained in solubility experiment after 24 h HAL 1-T 2 3B 4 5 6 7 8 9 hydrochloride salt saccharinate salt
crystalline forms
abs coeff (mM−1 cm−1)
HAL 1, OA salt 2, BA salt 3B, SA salt 4, 4HBA salt 5, 34DHBA salt 6, 35DHBA salt 7, MES salt 8, BES salt 9, TOS salt hydrochloride salt saccharinate salt
14.05 13.92 14.73 29.03 22.62 17.64 13.03 13.77 11.45 14.22
