The preparation and characterization of multi-component systems in drug pre-formulation

The supramolecular derivatisation, via co-crystallization and cyclodextrin (CD) inclusion of three active pharmaceutical ingredients (APIs), was attempted with the aim of generating new solid forms with potential pharmaceutical application. The APIs under investigation included allopurinol (used for the treatment of gout and kidney stones), 6-thioguanine (used to treat acute myelogenous leukaemia) and valproic acid (for treatment of epilepsy and bipolar disorders). Allopurinol and 6-thioguanine were fairly intractable, yielding very limited results following co-crystallization trials with a series of co-formers. However, a new polymorph of one of the co-formers, namely isonicotinamide, was discovered serendipitously and thoroughly characterized using thermal analysis and single crystal X-ray diffraction. Phase solubility studies with a variety of CDs showed that the poor aqueous solubility of allopurinol and 6-thioguanine was not significantly modified in the presence of CD solutions. However, a more accurate aqueous solubility value for 6-thioguanine was achieved, namely 0.078 ± 0.003 mg.cm-3 at 25 o C. Six new CD complexes of valproic acid (VAL) were isolated by kneading and/or coprecipitation methods and characterized by thermal analysis, powder X-ray diffraction and spectroscopic (1H NMR and FT-IR) techniques. The six CD complexes (with host-guest stoichiometries in parentheses) included -CD·VAL (2:1), -CD·VAL (1:1), -CD·VAL (4:3), DMB·VAL (1:1), TMB·VAL (1:1) and TMA·VAL (1:1). The -CD·VAL, -CD·VAL, and -CD·VAL complexes were assessed for their ability to alter the aqueous solubility of the drug at 23 o C. The SCD/So ratios for these CD complexes (SCD being the solubility of VAL in the form of the CD complex and So the solubility of pure VAL) were 0.39, 0.42 and 0.41 respectively and thus CD complexation reduced the aqueous solubility of valproic acid. Single crystal X-ray structures of four of the CD-valproic acid complexes were determined, those with native CDs featuring fully disordered guest molecules, while those with permethylated -CD and dimethylated -CD revealed the modes of inclusion of the drug unequivocally

The supramolecular derivatisation of pharmaceutically relevant compounds via co-crystallization and cyclodextrin inclusion complexation

The supramolecular derivatisation of pharmaceutically relevant compounds via co-crystallization and cyclodextrin (CD) inclusion complexation was attempted in order to produce new solid forms of these compounds for potential pharmaceutical applications. The pharmaceutically relevant compounds investigated included (a) three drug leads, namely pyrido[1,2-a]benzimidazole derivatives [displaying activity against schistosomiasis (bilharzia)], (b) two steroidal compounds, namely -estradiol (used for hormonal therapy and treatment of breast and prostate cancer), and progesterone (used for hormonal therapy), and (c) the potent antioxidant pterostilbene (displaying anti-cancer activity inter alia). Six new solid forms of the pyrido[1,2-a]benzimidazole derivatives resulted from their interaction with partner molecules L-malic acid and nicotinamide using 1:1 molar ratios of the starting materials. They were characterised by powder X-ray diffraction, thermal analysis and spectroscopic (FT-IR and 1H NMR) techniques. Preliminary solubility studies indicated that for five of the forms, aqueous solubility increases for the drug leads in the range 2- to 20-fold were achieved. In addition, amorphous forms of the three pyrido[1,2-a]benzimidazole derivatives were prepared via grinding and also assessed for aqueous solubility improvement, with the result that only one of them indicated a 2-fold aqueous solubility increase. In addition, nine new hydrated CD inclusion complexes with guests -estradiol (BES), progesterone (PRO) and pterostilbene (PTB), were isolated using kneading and/or co-precipitation methods, and analysed using thermal analysis, powder X-ray diffraction and 1H NMR analytical techniques. The CD inclusion complexes (with host-guest stoichiometries in parentheses) included -CD·BES (2:1), - CD·BES (1:1), dimethylated -CD·BES (1:1), -CD·PRO (2:1), -CD·PRO (3:2), dimethylated -CD·PRO (1:1), -CD·PTB (1:1), -CD·PTB (1:1) and permethylated -CD·PTB (1:1). The -CD·BES, -CD·BES, - CD·PRO and -CD·PRO inclusion complexes were assessed for their ability to improve the aqueous solubility of the respective steroids at 27 o C. The SAPI(CD)/SAPI ratios for these CD complexes (SAPI(CD) indicating the solubility of each steroid in the form of the CD complex and SAPI the solubility of the pure steroid), were 21.3 0.1, 6.1 0.3, 5.5 0.1 and 19.9 0.1 respectively, thus indicating that CD inclusion complexation increased the aqueous solubility of both steroids. Phase solubility studies of pterostilbene (PTB) with sulfobutylether -CD (SBEBCD) and randomly methylated -CD (RAMEB), indicated that the low aqueous solubility of PTB could be enhanced by factors of 1431 and 1356 respectively using 20 mM concentrations of SBEBCD and RAMEB at 25 o C. Single-crystal Xray structures of six of the new CD inclusion complexes were elucidated, -CD·BES, -CD·PRO and - CD·PRO featuring severely disordered guest molecules, while analysis of -CD·PTB, DMB·BES and DMB·PRO revealed the detailed modes of guest inclusion of the respective drugs unequivocally