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

View of chlorothiazide potassium: (a) dihydrate (CTZK form II), and (b) monohydrate hemiethanolate (CTZK form IV) by Ortep visualisation. 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...

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Published in:	European journal of pharmaceutical sciences 2011-02, Vol.42 (3), p.220-229
Main Authors:	Paluch, Krzysztof J., Tajber, Lidia, McCabe, Thomas, O’Brien, John E., Corrigan, Owen I., Healy, Anne Marie
Format:	Article
Language:	eng
Subjects:	Biological and medical sciences Calorimetry (DSC) Calorimetry, Differential Scanning Chlorothiazide - chemistry Chlorothiazide potassium Crystal structure Crystallography, X-Ray General pharmacology Mass Spectrometry - methods Medical sciences Microscopy, Electron, Scanning Moisture sorption Molecular Structure NMR spectroscopy Pharmaceutical technology. Pharmaceutical industry Pharmacology. Drug treatments Salts Solid state characteristics Solvate Spectroscopy, Fourier Transform Infrared
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Summary:	View of chlorothiazide potassium: (a) dihydrate (CTZK form II), and (b) monohydrate hemiethanolate (CTZK form IV) by Ortep visualisation. 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±1.82mg/ml, approximately 400-fold higher than chlorothiazide, indicating a biopharmaceutical advantage associated with the potassium salt form.
ISSN:	0928-0987 1879-0720