Olimpia Maria Martins Santos

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.

The form II of the antihypertensive drug chlorthalidone

Racemic mixtures of chlorthalidone (CTD) have been structurally elucidated in three crystal forms (space group P), namely, Form I, Form III (both true polymorphs) and a chloroform solvate. Here, we have structurally characterized the Form II, which, in contrast to the known forms, individual crystals are pure enantiomers. However, the Form II bulk product from spontaneous chiral resolution upon crystallization contains a mixture of crystals as a conglomerate, half of which consists solely of the (R)-enantiomer, the other half the (S)-enantiomer. Form II was solved in the space group P21 with one (R)-enantiomer unit in its asymmetric unit resembling that of Form III in terms of the chlorobenzenesulfonamide moiety conformation. Even though the (R)-enantiomer has been chosen for the single-crystal structure determination experiment, chiral chromatography and optical rotation data have inferred the conglomerate nature of Form II. Concerning the crystal packing of Form II, all hydrogen bonding functionalities of the sulfonamide group are saturated into the assembly of helical ribbons growing along the [010] direction, a supramolecular motif which is not found in the known crystal phases of the drug. Moreover, Form II shows packing similarity to the chloroform solvate mainly because the hydrogen bonding patterns of their isoindolinyl functionalities. The isoindolinyl stacking also occurs similarly in Form II and in the solvate form, with bends between the planes calculated through those moieties of stacked molecules of ca. 28° and 24°. In summary, we believe that the structural knowledge of Form II concerns new outlooks not only into the solid-state properties of CTD but also into its medicinal chemistry, e.g., regarding pharmacological profiles of the conglomerate.

Structure, Solubility and Stability of Orbifloxacin Crystal Forms: Hemihydrate versus Anhydrate

Orbifloxacin (ORBI) is a widely used antimicrobial drug of the fluoroquinolone class. In the official pharmaceutical compendia the existence of polymorphism in this active pharmaceutical ingredient (API) is reported. No crystal structure has been reported for this API and as described in the literature, its solubility is very controversial. Considering that different solid forms of the same API may have different physicochemical properties, these different solubilities may have resulted from analyses inadvertently carried out on different polymorphs. The solubility is the most critical property because it can affect the bioavailability and may compromise the quality of a drug product. The crystalline structure of ORBI determined by SCXRD is reported here for the first time. The structural analysis reveals that the ORBI molecule is zwitterionic and hemihydrated. ORBI hemihydrated form was characterized by the following techniques: TG/DTA, FTIR-ATR, and PXRD. A second crystalline ORBI form is also reported: the ORBI anhydrous form was obtained by heating the hemihydrate. These ORBI solid forms were isomorphous, since no significant change in unit cell and space group symmetry were observed. The solid-state phase transformation between these forms is discussed and the equilibrium solubility data were examined in order to check the impact of the differences observed in their crystalline structures.

A Dissolution Test for Finasteride in Immediate-Release Capsules

In vitro dissolution tests for solid oral dosage forms are extremely important to ensure the quality of these products. However, no dissolution test has been reported for finasteride (FNS) in immediate-release capsules. The aims of this work were to optimize a dissolution method for FNS capsules, validate the analytical method, and evaluate three different commercial products. The best in vitro dissolution profile was achieved using water as the dissolution medium with a basket stirrer at 100 rpm. The quantitative determination was performed by high performance liquid chromatography (HPLC) at 210 nm. All validation parameters were satisfactory. The application of the method to commercial products showed the discriminatory power of the dissolution method. Because there is no monograph for FNS in capsules, this study illustrates the importance of an official dissolution test for FNS in capsules and the need to standardize the composition of the excipients contained in these commercial products. INTRODUCTION In vitro dissolution tests for immediate-release solid oral dosage forms, such as tablets and capsules, are extremely important because these tests are essential to evaluate the lot-to-lot quality of a drug product, to guide the development of new formulations, and to ensure continuing product quality and performance after certain changes (e.g., formulation, manufacturing process, site of manufacture, and scale-up of the manufacturing process) (1). For these reasons, progressively more emphasis has been placed on dissolution testing within the pharmaceutical industry and by regulatory authorities (2). Despite the importance of dissolution tests in ensuring the quality of medicines, several drug products that are widely commercialized throughout the world lack official dissolution tests. Finasteride (FNS) is a relevant example because no dissolution test is reported in the literature or in pharmacopeias for immediate-release capsules of this medication. FNS capsules are widely marketed and are prepared for medical reasons (e.g., avoiding an excipient to which a patient is allergic or obtaining a dosage level that is not marketed). FNS is N-(1,1-dimethylethyl)-3-oxo-4-aza-5α-androst1-ene-17β-carboxamide (Figure 1), a specific competitive inhibitor of steroid type-II 5α-reductase, an intracellular enzyme that converts testosterone to dihydrotestosterone (DHT) and is widely used for the treatment of benign prostatic hyperplasia (BPH) (3), prostate cancer (4), and androgenetic alopecia (5–8). A daily dose of 5 mg has been used for the treatment of BPH and prostate cancer, and a 1-mg dose has been used for the treatment of androgenetic alopecia. FNS has a molecular formula of C23H36N2O2, a molecular weight of 372.6, and a log Po/w of 3.03. According to the Biopharmaceutics Classification System (BCS), FNS is a Class 2 drug having low solubility and high permeability (9). Multiple analytical procedures have been reported for the analysis of FNS in pharmaceutical preparations when it is present as a single active ingredient or in combination dosage forms, using spectrophotometry (10–12), thin-layer chromatography (13, 14), infrared spectrophotometry (15), polarography (16), voltammetry (17), gas chromatography (18), gas chromatography–mass spectrometry (19), high performance liquid chromatography (HPLC) (20–23), and ultra-high performance liquid chromatography (UHPLC) (24, 25). Because of the importance of in vitro dissolution tests for immediate-release solid oral dosage forms and the lack of a dissolution test for FNS compounded capsules, the aims of this work were to optimize a dissolution method *Corresponding author. e-mail: olimpia_martins@yahoo.com.br Figure 1. Chemical structure of finasteride. dx.doi.org/10.14227/DT200313P25

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.

Quality evaluation of the Finasteride polymorphic forms I and II in capsules.

Finasteride (FNS) is a specific competitive inhibitor of steroid type-II 5α-reductase and is widely used for the treatment of benign prostatic hyperplasia, prostate cancer, and androgenetic alopecia. FNS has two polymorphic forms identified as Form I and Form II. It is known that polymorphism can cause significant differences in the physicochemical properties of a compound such as melting point, density, morphology, solubility, and color. Thus, proper qualitative and quantitative monitoring of the solid-state forms is crucial to ensure high-quality products. There are no published papers studying the influence of the FNS polymorphs on the physicochemical quality of capsules. Furthermore, the available analytical methods are time-consuming, expensive, use buffer or do not demonstrate stability-indicating capacity. The aim of this work was to validate a rapid high-performance liquid chromatography (HPLC) method to evaluate FNS in capsules and to study the physicochemical properties of polymorphic forms, evaluating their possible influence in the dissolution profile and stability of FNS in capsules. Capsules containing Forms I and II of FNS were prepared and subjected to quality control studies, dissolution profiles and a stability study at 50°C. A significant effect of polymorphism on the FNS solubility and dissolution properties was observed. These results suggest that changes in the effects of FNS can occur if a suitable control study is not performed on the raw material used to produce the capsules.

Estabelecimento de condições para ensaio de dissolução de cápsulas de cinarizina empregando planejamento fatorial

This work describes the establishment of dissolution test conditions for 75 mg cinnarizine capsules using a multivariate approach. A 23 full factorial design was carried out to achieve the best conditions and HCl 0.1 mol L-1 as dissolution medium, basket as apparatus at 100 rpm and collect time at 30 min were considered adequate. The quantification was carried out by spectrophotometry at 251 nm. Both dissolution procedure and analytical method were validated and all parameters were within the acceptable limits. Since there is no official monograph for this pharmaceutical product, this dissolution test could be applied for quality control routine.