The Development and Validation of a Dissolution Method for ...

1 16 DissolutionTechnologies| AUGUST 2004 The Development and Validation of a Dissolution Method for clomipramine Solid Dosage FormsMehdi Ansari 1,3, Maryam Kazemipour 2, Javad Talebnia1email: IntroductionDrug absorption from solid dosage forms after oraladministration depends on the release of the drugsubstance from the drug product, the Dissolution orsolubilization of the drug under physiological conditions,and the permeability across the gastrointestinal of the critical nature of the first two of these steps,in vitro Dissolution may be relevant to the prediction of invivo performance. Based on this general consideration, invitro Dissolution tests for immediate release solid oraldosage forms are used: (a) to assess the lot-to-lot quality ofa drug product; (b) to assess the stability of the drug prod-uct; (c) to ensure continuing product quality and perfor-mance after certain changes, such as changes in the formu-lation, the manufacturing process, the site of manufacture,and the scale-up of the manufacturing process; and (d) todevelop new formulations.

2 In formulation Development , Dissolution testing can aid in the selection of excipients,help optimize the manufacturing process, and enable for-mulation of the test product to match the release of thereference product [1 and 2]. Dissolution testing has emerged in the pharmaceuticalfield as a very important tool to characterize drug productperformance. The Dissolution test is an analytical techniquethat has undergone significant equipment modificationsand improvements spanning the last decade. Dissolutionhas become an important and widely utilized test receivingmore emphasis worldwide from regulatory authorities dur-ing the last 15 years. The significance of a Dissolution test isbased on the fact that for a drug to be absorbed and avail-able to the systemic circulation, it must previously be dis-solved [3].

3 Therefore, Dissolution tests are used not only forquality control of finished products, but also to assess sev-eral stages of formulation Development , for screening andproper assessment of different formulations [4]. Basically,the Dissolution test makes it possible to assess the dissolu-tion properties of the drug itself and thereby to select themost appropriate excipients and to optimize proportionsamong them to obtaining the desired drug release behav-ior. Moreover, when an in vitro/in vivo correlation is avail-able, Dissolution can be used as a test to reflect thebioavailability of a product in humans and therefore todetermine the actual bioequivalence of different productscontaining the same drug at the same a preformulation study, preliminary testing condi-tions are commonly elaborated taking into considerationthe state of the art for Dissolution testing.

4 Different officialapparatus are available and, for each, Compendia, , USP,BP, and EP, report detailed specifications in both generalchapters [5 and 6] and individual monographs on solid oraldosage forms. Dissolution tests of conventional dosageforms have been successfully implemented, and formalguidelines exist which provide useful recommendations fortheir evaluation [7].In any case, it is important to point out that none of thepurposes for which Dissolution tests are used can be ful-filled by an in vitro test without sufficient reliability, wherethis is defined as a system being experimentally sound,yielding precise, accurate and repeatable results [8]. Arecent international collaborative study indicated that drugAbstractDissolution testing has emerged in the pharmaceutical field as a very important tool to characterize drug product perfor-mance.

5 clomipramine HCl as a frequently used antidepressant has no Dissolution Method in its monograph in BP or USP. Invitro Dissolution tests of solid oral dosage forms of clomipramine were performed by various methods using different testconditions but always under sink conditions. Release profiles of different dosage forms of clomipramine show that releaserate from capsules is much faster than from film coated tablet and that release from film coated tablet is faster than from thesugar-coated tablet. Dissolution of almost all forms was complete at 45 minutes. The in vitro release profiles of various testswere compared for their similarity using the f2 test. Results of this test indicate that in most cases Dissolution profiles of thedifferent products were significantly different from each other.

6 Under certain conditions, tablets had a more discriminatingprofile than capsules under the same test conditions. A Method using HCl as the Dissolution medium in USP Apparatus 2 andstirring speed of 75 rpm, for all solid oral dosage forms of clomipramine could reliably discriminate among different products,if they are truly different. With these conditions, more than 80% of the label amount is released over 30 of Pharmaceutics, Faculty of Pharmacy, Kerman MedicalSciences University, Kerman, Iran2 Department of Chemistry, Faculty of Sciences, Kerman Azad University,Kerman, Iran3 Corresponding author, Department of Pharmaceutics, Faculty of Pharmacy,Kerman Medical Sciences University, Kerman, Iran | AUGUST 2004dissolution testing is a highly variable technique [9]. As aconsequence, in many cases the impact of formulation ormanufacturing changes on drug release properties maynot be detected, or, on the contrary, not true differences,but rather differences caused by test variability, could berecorded.

7 Thus, careful control of experimental conditionsis necessary in order to suitably reduce test-to-test variabili-ty and improve test reproducibility and Validation of the Dissolution test can be divided intotwo parts. The first regards equipment Validation ; equip-ment has to be calibrated taking into consideration thespecifications for geometry and alignment of the dissolu-tion apparatus [10]. The second concerns test Validation ; itrequires the study of the performance parameter precision[5]. The evaluation of precision is very important in order toassess the reliability of the data obtained by the dissolutiontest. In fact, it is true that a more discriminating dissolutionmethod is preferred, but it is also true that a reliable disso-lution test is of utmost importance. A Dissolution test witha good precision, for example, makes it possible to effi-ciently compare different alternative formulation candi-dates to select the dosage form with the most suitable andreproducible drug release profile.

8 At the time of the disso-lution test Development , however, in vivo human data isnormally not available. Instead, prior to the human clinicalstudies, Dissolution data must usually be generated with-out the benefit of comparative rankings between formula-tions or lots, estimated in vivo absorption rates, or anyother information that could be used to guide the develop-ment of a discriminating Dissolution test [11 and12]. clomipramine is a chlorinated analogue of imipraminewith both antidepressant and anti-obsessional properties[13]. clomipramine is an organic base of highly lipophilicnature. Its HCl salt is freely soluble in water. There is no offi-cial Method for determination of Dissolution rate ofclomipramine hydrochloride solid oral dosage forms. Areview of the literature indicated that there was no report-ed Dissolution Method for clomipramine USP I (Basket) - USP II (Paddle)MediumHCl N Phosphate Buffer at pHSpeed50 rpm -75 rpmTable 1.

9 Dissolution conditions that were used in thisstudy See Development and continued on page 2020 DissolutionTechnologies| AUGUST 2004 Consequently, the in-house Development of a precise, vali-dated, and reliable Dissolution Method for clomipraminesolid oral dosage forms was necessary in order to supportthe product Development and quality control efforts. Thispaper describes the Development and Validation of the dis-solution methodology for clomipramine solid MaterialsClomipramine HCl pharmaceutical grade was kindlydonated by Shahr Daru Pharmaceutical Co. (Iran);Hydrochloric acid (Merck, Darmstadt, Germany), was usedas received. clomipramine HCl film coated tablets wereobtained from Shahr Daru Pharmaceutical Co. (Iran);labeled to contain 10 mg, 25 mg, and 50 mg ClomipramineHCl.

10 Anafranil capsules contained 10 mg 25 mg, and 50mg clomipramine HCl manufactured by Novartis(Switzerland). Anafranil sugar coated tablets labeled tocontain 10 mg clomipramine HCl were obtained from CibaGeigy (England). Doubly distilled water was used through-out the Preparation of standard solutionsClomipramine stock standard solution was prepared at aconcentration of 100 mg/mL in water. The clomipraminestock standard solution was diluted to obtain the knownstandard concentrations of 5, 10, 15, 20, 25, 30, 40, and 50mg/mL in either 1 N HCl or pH phosphate buffer. Thebuffer was prepared by mixing 50 mL of M potassiumdihydrogen orthophosphate with mL of M sodi-um hydroxide volumetric solution and diluting to 200 mLwith water. UV absorbance of each standard solution wasmeasured spectrophotometrically (UV/Vis spectropho-tometer Shimadzu 2100, Tokyo, Japan) at 252 nm with themean data (n=6) used for the calibration curve.