Discriminatory Dissolution Test for Tablets Containing a- and b-Thalidomide Polymorphs

Over the years, thalidomide has been prescribed for an increasing number of diseases, including multiple myeloma and erythema nodosum leprosum. In Brazil and other countries, thalidomide is available in tablets, and there is no official dissolution testing available for this dosage form. Considering this, a dissolution method was developed and validated for tablets containing 100 mg of each polymorph using 1-L vessels to verify that it can differentiate between polymorphs, since drug product is supposed to be formulated with the α form. In addition, the possibility of using smaller volumes of dissolution medium was also explored. This method was compared with the USP dissolution method for thalidomide capsules (4-L vessel) with independent models using difference and similarity factors as well as dissolution efficiency. Dissolution kinetics was evaluated using zero-order, first-order, Higuchi, and Korsmeyer–Peppas models. The kinetic parameters and the suitability of the models for experimental data were evaluated. The developed dissolution method was fully validated. It allowed a better discrimination of thalidomide polymorphs than the USP method for the formulations tested. Considering that it uses a conventional dissolution apparatus with 1-L vessels and there is no method described for tablets, it can be used for quality control of thalidomide in this dosage form. INTRODUCTION Many solid drugs exist in different physical forms. Polymorphism is often characterized as a drug’s ability to exist as two or more crystalline phases that have different arrays, molecular conformations, or both (1, 2). Thalidomide (Figure 1) has two known polymorphic forms, α and β, each one isolated by crystallization using different conditions (3, 4). Their characteristics in the solid state exert a significant influence on the drug dissolution rate. Drug polymorphs may have different aqueous solubilities and rates of dissolution. When these differences are sufficiently large, bioavailability may change, and could lead to deviations in product quality (1, 5, 6). For these reasons, it is essential to pay extra attention to drugs presenting polymorphism during the development of generic medications (1, 2). The low solubility of thalidomide in water, which is around 50 μg/mL for the racemic mixture (7, 8), led to the development of thalidomide exclusively for oral use. The polymorphic form of drugs with poor aqueous solubility, such as thalidomide, must be controlled to ensure product quality. It is therefore important for the dissolution method to be capable of detecting changes in the analyzed product, and it is mainly important to monitor low solubility drugs for critical parameters of the formulation (9). Thus, this work aimed at the development of a discriminative dissolution method able to detect differences in dissolution profiles between tablet formulations obtained from αand β-thalidomide polymorphs. The method will be compared to that proposed by USP (10). MATERIAL AND METHODS Materials Thalidomide reference standard was acquired from USP (Lot FOC 107, Rockville, MD, USA). Drug substances of αand β-thalidomide were kindly donated by Microbiologica (lots TH.T.004 and SEE–052, respectively). Sodium lauryl sulfate (SLS) was purchased from Synth (São Paulo, Brazil). Polyoxyethylene lauryl ether (Brij 35) and hydrochloric acid were acquired from Vetec (Rio de Janeiro, Brazil). Acetonitrile (HPLC grade) was purchased from Honeywell *Corresponding author. e-mail: [email protected] Figure 1. Chemical structures of R-(+)-thalidomide and S-(-)-thalidomide. dx.doi.org/10.14227/DT200113P19