Preparation and characterisation of novel chlorothiazide potassium solid-state salt forms: intermolecular self assembly suprastructures

Abstract

Chlorothiazide (CTZ) is a poorly soluble diuretic agent. The aim of the present work was to produce and characterise a potassium salt form of chlorothiazide which has the potential advantages of improved aqueous solubility and potassium supplementation. A number of novel potassium salt forms of CTZ (CTZK) were prepared: CTZK monohydrate (form I), CTZK dihydrate (form II), anhydrous CTZK (form III), CTZK monohydrate hemiethanolate (form IV) and a desolvate of CTZK monohydrate hemiethanolate (form V). These salt forms were characterised by thermal analysis, PXRD, NMR, elemental analysis, FTIR, Karl Fisher titrimetry, ICP-MS and GC-MS. The ethanol-free CTZK forms were also characterised by dynamic vapour sorption analysis (DVS). CTZK form I was stable (in the DVS) over the range 0% to 60% RH. The dihydrate form of the salt was stable (in the DVS) over a broader range of relative humidities, 10 to 90%RH at 25?C. CTZK form II was less hygroscopic at high humidities (70-90% RH) than the previously reported CTZNa dihydrate. Single crystal X-ray analysis indicated that chlorothiazide potassium, crystallised from water or water/acetone mixture, formed a dihydrated polymeric-like intermolecular self-assembly (ISA) suprastructure. The ISA coordination was determined to be: (CTZ)3?K?(H2O)2(CTZ)2?(H2O)2?K?(CTZ)3 (monoclinic, space group: C2/c, single crystal cell parameters: a = 18.328(4) ?, b = 7.3662(16) ?, c = 19.993(5) ?, ?= 90?, ?= 99.729(3)?, ? = 90?). When CTZK was crystallised from ethanol, a monohydrate hemiethanolate ISA was formed, described as (CTZ)3?K?CTZ?(H2O)2?CTZ?K?(CTZ)2 (triclinic, space group: P-1, single crystal cell parameters: a = 7.078(3) ?, b = 9.842(5) ?, c = 21.994(11) ?, ? = 87.522(13)?, ?= 84.064(14)?, ?= 78.822(12)?). The aqueous solubility of CTZK dihydrate, was determined to be 78.71 ? 1.82 mg/ml, approximately 400-fold higher than chlorothiazide, indicating a biopharmaceutical advantage associated with the potassium salt form.