1 Stable Crystalline Salts of Haloperidol: A Highly Water-Soluble 2 Mesylate Salt 3 Lalit Rajput* 4 Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India 5 * S Supporting Information 6 ABSTRACT: Haloperidol, an antipsychotic drug, was screened for new 7 solid crystalline phases using high throughput crystallization in pursuit of 8 solubility improvement. Due to the highly basic nature of the API, all the 9 solid forms with acids were obtained in the form of salts. Eleven crystalline 10 salts in the form of oxalate (1:1), benzoate (1:1), salicylate (1:1 and 1:2), 4- 11 hydroxybenzoate (1:1), 4-hydroxybenzoate ethyl acetate solvate (1:1:1), 3,4- 12 dihydroxybenzoate (1:1), 3,5-dihydroxybenzoate (1:1), mesylate (1:1), 13 besylate (1:1), and tosylate (1:1) salt were achieved. There is an insertion of 14 carboxylate or sulfonate anion into the hydrogen bonding pattern of 15 haloperidol. The salts with the aliphatic carboxylic acids were found to be 16 more prone to form salt hydrates compared with aromatic carboxylate salts. 17 All the salts were subjected to solubility measurement in water at neutral 18 pH. There was no direct correlation observed between the solubility of the 19 salt and its coformer. All the salts are stable at room temperature as well as after 24 h slurry experiment except the oxalate salt, 20 which showed an unusual phase transformation from its hydrated form to the anhydrous form. A structure-property relationship 21 was examined to analyze the solubility behavior of the solid forms. 22 ■ INTRODUCTION 23 Crystal engineering has provided a new and efficient approach 24 for the tuning of the physicochemical properties of active 25 pharmaceutical ingredients (API), and this in turn has a direct 26 application in the pharmaceutical industry. 1 APIs can exist in 27 the form of polymorphs, salts, cocrystals, hydrates, or solvates 28 and may exhibit distinct physical properties compared with the 29 parent API. 2 Among these, salt or cocrystal formation is 30 nowadays commonly put into practice in the pharmaceutical 31 industry where the API is crystallized with a generally regarded 32 as safe (GRAS) coformer. 3 The coformer can modulate the 33 stability, solubility, bioavailability, and tableting attributes of the 34 API. 4 Currently almost 40% of marketed drugs face the major 35 problem of poor aqueous solubility, which affects the 36 absorption in the GI track. 5 Solubility of an API is related to 37 issues such as bioavailability and permeability. Several methods 38 such as making an amorphous phase by using polymer, solid 39 dispersion, additives, excipients, and cyclodextrin can be 40 implemented to improve the solubility of an API. 6 However, 41 salt or cocrystal formation still remains as one of the best 42 approaches for solubility improvement without disturbing the 43 inherent pharmacological properties of the API. To design 44 cocrystals or salts, a crystal engineering approach based on 45 supramolecular synthons is advantageous. 7 Cocrystal formation 46 can improve the solubility by 100 times, whereas salts can 47 modulate the solubility almost 1000-fold. 8 Salt formation is the 48 most common method for improving solubility and today more 49 than 50% of APIs are marketed as salts. 9 However, salt 50 formation is limited to ionizable APIs exhibiting acidic or basic 51 functional sites. The formation of salt or cocrystal can be 52 predicted by the ΔpK a rule (ΔpK a =pK a(base) - pK a(acid) ). 10 It is 53 assumed that if the ΔpK a < 0, a cocrystal will be formed while if 54 ΔpK a > 3 salt formation will ensure. In the intermediate range 55 of 0 < ΔpK a < 3, there is a possibility of formation of salt, 56 cocrystal, or salt-cocrystal continuum. This “rule of three” is 57 helpful to predict the outcome of a particular combination of 58 API and coformer. However, several groups have found that 59 this ΔpK a range can extend for particular systems, and the 60 maximum until now reported is -1 to 4. 11 61 In continuation of our efforts to improve the physiochemical 62 properties of APIs with a crystal engineering approach, we have 63 selected an antipsychotic drug, haloperidol (HAL). 12 Haloper- 64 idol, 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4-fluoro- 65 phenyl)-butan-1-one, is a butyrophenone derivative and 66 functions as an inverse agonist of dopamine in the biological 67 system. 13 Generally it is prescribed for the treatment of 68 schizophrenia. It is on the list of World Health Organization 69 essential medicines for basic health care. 14 Haloperidol (trade 70 name Haldol) is a BCS class II drug and exhibits low solubility 71 (14 mg/L) and high permeability (log P = 4.3). 15 It is almost 72 insoluble in water over a wide range of pH and is stable at room 73 temperature. The flexible molecule has a central cyclohexane 74 ring with tertiary amine nitrogen, an alcoholic hydroxy, and 75 s1 ketone functionality (Scheme 1). In the crystal structure of Received: July 2, 2014 Revised: August 18, 2014 Article pubs.acs.org/crystal © XXXX American Chemical Society A dx.doi.org/10.1021/cg500982u | Cryst. Growth Des. XXXX, XXX, XXX-XXX lmh00 | ACSJCA | JCA10.0.1465/W Unicode | research.3f (R3.6.i5 HF03:4230 | 2.0 alpha 39) 2014/07/15 09:23:00 | PROD-JCAVA | rq_3900693 | 9/05/2014 11:21:14 | 10 | JCA-DEFAULT