Solid state characterization, solubility, intrinsic dissolution and stability behavior of allopurinol hydrochloride salt.

Since each solid form of an active pharmaceutical ingredient (API) can exhibit particular physicochemical properties, the objectives of this work were to characterize and study the solubility/stability properties of allopurinol hydrochloride salt (ALO-HCl) for the first time. ALO-HCl was obtained through an unreported recrystallization process and studied by X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). All characterization techniques were effective for the differentiation of ALO-HCl from the preferred pharmaceutical form (ALO). DSC and TGA studies showed a solid-state conversion from ALO-HCl to ALO upon HCl loss. Solubility and dissolution tests showed that ALO-HCl converts to ALO in aqueous media. Moreover, the effect of the common ion decreased the amount of drug released from ALO-HCl during the intrinsic dissolution assay in HCl medium. The stability studies showed a partial conversion from ALO-HCl to ALO after 6 months of storage. The results indicate that comparative studies between crystalline forms of APIs are of great importance, as they contribute to the understanding of aspects related to the quality of medicines.

Multivariate development and validation of a stability-indicating HPLC method for the determination of glimepiride in tablets.

This paper describes the multivariate development of a stability-indicating HPLC method for the quantification of glimepiride in pharmaceutical tablets. Full factorial design, Doehlert design, and response-surface methodology were used in conjunction with the desirability function approach. This procedure allowed the adequate separation of glimepiride from all degradant peaks in a short analysis time (about 9 min). This HPLC method uses potassium phosphate buffer (pH 6.5; 27.5 mmol/L)-methanol (34 + 66, v/v) mobile phase at a flow rate of 1.0 mL/min and UV detection at 228 nm. A Waters Symmetry C18 column (250 x 4.6 mm, 5.0 pm) at controlled room temperature (25 degrees C) was used as the stationary phase. The method was validated according to International Conference on Harmonization guidelines and demonstrated linearity from 2 to 40 mg/L glimepiride, selectivity, precision, accuracy, and robustness. The LOD and LOQ were 0.315 and 1.050 mg/L, respectively. The multivariate strategy adopted in this work can be successfully applied in routine laboratories because of its fast optimization without the additional cost of columns or equipment.

Identification and proportion of the enantiomers of the antihypertensive drug chlortalidone in its Form II by high quality single-crystal X-ray diffraction data.

Chlortalidone (CTD) is a diuretic drug largely used as part of antihypertensive therapies. It is marketed as an equimolar mixture of its enantiomers in the racemic crystal phase named Form I, despite of the higher aqueous solubility of another crystal form. The latter, named Form II, was thought to contain both enantiomers as a racemic conglomerate, i.e., in the form of a mixture of crystals, half of which consists solely of the (R)-enantiomer, the other half the (S)-enantiomer. The occurrence of both enantiomers in individual crystals of CTD Form II was demonstrated in this study. Spontaneous resolution does really occur upon crystallization, as presumed previously even without physical evidence of the (S)-enantiomer. Both (R) and (S)-enantiomers were successfully identified as two domains of a twinned by inversion single crystal of CTD Form II. A reliable Flack parameter of 0.14(4) allowed to determine the proportion of the enantiomers in the crystal, which is formed with 86% of the (R)-enantiomer and 14% of the (S)-enantiomer.

Analysis of chlorthalidone polymorphs in raw materials and tablets and the effect of forms I and II on the dissolution properties of drug products.

Chlorthalidone (CTD) is an antihypertensive drug and exhibits four crystalline forms: I, II, III and IV. In this paper, the incidence of CTD polymorphs in raw materials and in tablets as well as the solubility and dissolution properties of forms I and II have been studied. Raw materials were named as A, B, C, D, and E and tablets as Reference, G1, G2 and S. Using powder X-ray diffraction and infrared spectroscopy analyses we found that A, B, E, Reference and G1 contain CTD form I; C, D and S contain predominantly form II; and G2 contain a mixture of both forms. Solubility experiments showed that form II is up to 49% more soluble than form I and dissolution studies showed a significantly effect of the polymorphism on the dissolution of CTD from tablets. Based on these results, it was concluded that only the CTD form I is acceptable for preparation of tablet form. Moreover, we proposed the polymorphic quality control of CTD raw materials and tablets.

Lamivudine salts with improved solubilities.

To optimize solubility of drugs, current strategies mainly focus on engineering and screening of smart crystal phases. Two salts of the anti-human immunodeficiency virus (HIV) drug lamivudine--namely, lamivudine hydrochloride and lamivudine hydrochloride monohydrate, were prepared in the course of screening the crystallization conditions of lamivudine duplex, an uncommon DNA-mimic, double-stranded helical structure made up of partially protonated drug pairs. Here, water solubilities of lamivudine hydrochloride, lamivudine hydrochloride monohydrate, and lamivudine duplex are reported. The aqueous solubility of this anti-HIV drug was significantly increased in both salts and also in lamivudine duplex in relation to the water solubility of lamivudine form II. In comparison with the lamivudine form II incorporated into therapeutic formulations, the drug solubility was increased at a temperature of 299 ± 2 K by factors of 1.2, 3.3, and 4.5 in lamivudine hydrochloride, lamivudine hydrochloride monohydrate, and lamivudine duplex, respectively, demonstrating that this solid-state property of lamivudine can be improved by crystal engineering strategies. Solubility profiles were understood on the basis of structural and solvent-solute interaction approaches. At last, correlations between solubility and crystal structures allowed for a rational approach to understand how this physicochemical feature could be enhanced by engineering new salts of the drug.

A discriminating dissolution method for glimepiride polymorphs.

Glimepiride, an oral antidiabetic drug, is practically insoluble in water and exists in two polymorphic forms, I and II, of which form II has higher solubility in water. Because the dissolution rate of drugs can depend on the crystal form, there is a need to develop discriminating dissolution methods that are sensitive to changes in polymorphic forms. In this work, a dissolution method for the assessment of 4 mg glimepiride tablets was developed and validated. The optimal dissolution conditions were 1000 mL of phosphate buffer (pH 6.8) containing 0.1% (w/v) of sodium dodecyl sulfate as the dissolution medium and a stirring speed of 50 rpm using a paddle apparatus. The results demonstrated that all the data meet the validation acceptance criteria. Subsequently, tablets containing forms I and II of glimepiride were prepared and subjected to dissolution testing. A significant influence of polymorphism on the dissolution properties of glimepiride tablets was observed. These results suggested that the raw material used to produce glimepiride tablets must be strictly controlled because they may produce undesirable and unpredictable effects.