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

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 0–60% RH. The dihydrate form of the salt was stable (in the DVS) over a broader range of relative humidities, 10–90% 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) Å, b = 7.3662(16) Å, c = 19.993(5) Å, α = 90°, β = 99.729(3)°, γ = 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) Å, b = 9.842(5) Å, c = 21.994(11) Å, α = 87.522(13)°, β = 84.064(14)°, γ = 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.

Graphical abstractView of chlorothiazide potassium: (a) dihydrate (CTZK form II), and (b) monohydrate hemiethanolate (CTZK form IV) by Ortep visualisation.Figure optionsDownload full-size imageDownload high-quality image (187 K)Download as PowerPoint slide