Developing a Discriminating Dissolution …

1 13 DissolutionTechnologies| FEBRUARY 2004 Developing a Discriminating DissolutionProcedure for a Dual Active PharmaceuticalProduct with Unique Solubility CharacteristicsLagace, ,2,Gravelle, ,Di Maso, McClintock, : testing is a required test currently used todemonstrate the performance of all solid oral dosageforms in which absorption of the drug is necessaryfor the product to exert a therapeutic effect (1). The chal-lenge for scientists working in a research and developmentenvironment is to develop a procedure that can not onlyguide the formulation development process but can alsobe used as a regulatory test to detect manufacturing devia-tions and to ensure product consistency at release andover the product s shelf life. The test must be rugged andreproducible and highlight only significant changes inproduct performance.

2 The robustness of the procedure isparticularly important since calibrated Dissolution bathsare allowed a variation of 2 rpm in the rotational speedof the apparatus. If a formulation is sensitive to smallchanges in rotational speed, then observed changes in thedissolution profile may simply reflect allowable instrumentvariation. The development of a Dissolution procedureinvolves selecting the Dissolution media, apparatus andagitation rate appropriate to the solubility of the active ingredient(s) is one of thekey aspects in the screening of possible dissolutionmedia. USP favors media related to physiological condi-tions, for example buffer solutions or diluted HCl ( N)(2). The Dissolution characteristics of the formulation areto be evaluated over the physiologic pH range of (1). For water-insoluble and sparingly water solubledrug products, use of a surfactant such as sodium laurylsulfate is recommended (3).

3 To ensure good mixing of the drug and excipients inthe Dissolution vessel, a suitable apparatus and rotationalspeed should be selected. The basket method (Apparatus1) is routinely used for capsule formulations at agitationspeeds of 50 and 100 rpm, while the paddle method(Apparatus 2) is used mostly for tablets dosage forms at50 and 75 rpm (1). In general, mild agitation conditionsshould be maintained during Dissolution testing to allowmaximum discriminatory power (4). In most cases, the dis-solution apparatus tends to become less discriminatingwhen operated at faster speeds that result in a flatterdrug release profile. However, for certain tablet formula-tions, the increased paddle speed results in a methodwith a higher Discriminating power by reducing the vari-ability of the data. Use of a low rotation speed couldresult in a lack of robustness in the data due to poorhydrodynamics in the Dissolution vessel and can becomemore a reflection of system artifacts such as coning ratherthan true formulation changes.

4 Visual observations areespecially useful during method development to under-stand the behavior of the tablet in the Dissolution agitation speed providing optimum hydrodynamicsin the vessel can be determined by comparison of the dis-solution profiles obtained by making small variations inpaddle speed (robustness experiments) as well as by chal-lenging the testing procedure through the use of mis-manufactured tablets (discriminatory power experi-ments). The final Dissolution procedure should be robustand should be able to distinguish small but real changesin the product agencies often consider USP Dissolution methods developed using the slowest paddle speed (50 rpm) to repre-sent the most appropriate operating condition since they tend to produce the steepest drug release profiles. A steep drugrelease profile is frequently assumed to provide optimum Discriminating power either to distinguish small variations in thetablet manufacturing process or to detect stability changes on storage.

5 However, for certain tablet formulations it has beendemonstrated that drug release profiles generated at 50 rpm can in fact be a reflection of system artifacts rather than adiscriminatory tool. Higher paddle speeds which result in flatter drug release profiles can, in some cases, more accuratelyreflect true formulation point is highlighted in the description of the development of a Dissolution method for a compressed tablet containingtwo active pharmaceutical ingredients (API). The selection of Dissolution medium for a tablet with two APIs having verydifferent solubility properties is detailed. The effects of paddle speed on system performance and method discriminatingpower are critically author, Department of Pharmaceutical Research andDevelopment, Merck Frosst Canada & Co., 16711 Trans Canada Hwy.

6 ,Kirkland, Quebec, H9H 3L1 CanadaTelephone: 514-428-3783, Fax: 514-428-2677, e-mail of Pharmaceutical Research and Development,Merck Frosst Canada & Co., 16711 Trans Canada Hwy., Kirkland, Quebec,H9H 3L1 | FEBRUARY 2004 Figure 1. Dissolution rate of (A) Active A and (B) Active B in various media using USP Apparatus II at 50 rpm and 37 oCFigure 2. Dissolution of Active A at (A) 50 5rpm and (B) 75 5rpmFigure 3. Visual observation of the Dissolution of Compound A/B at (A) 50 rpm and (B) 75 rpm after 15 min of paddle rotation15 DissolutionTechnologies| FEBRUARY 2004 ExperimentalReagentsAll preparations ( Dissolution media and mobile phase)were carried out using the following reagents: Milli-Qgrade water, hydrochloric acid (HCl), potassium biphtha-late (KHC6H4(COO)2, reagent grade), potassium phosphate(KH2PO4, reagent grade), sodium lauryl sulfate (SDS;CH3(CH2)10CH2 OSO3Na 99% pure; ACS grade), sodiumphosphate monobasic monohydrate (NaH2PO4 H2O,reagent grade).

7 Buffer solutions were prepared as described in theUnited States Pharmacopeia (USP, Edition 23), Reagents,Indications, and Solutions MethodologyExperiments were carried out using a manual DistekDissolution System equipped with paddles (USPA pparatus II) and amber Distek or Vankel Dissolution ves-sels. Clear Vankel PEAK vessels were also used to investi-gate coning. A Dissolution volume of 900 mL was used ata temperature of 37 oC. The procedure used paddlesat 50 5 rpm and 75 5 rpm. Samples were taken at 10,15, 20 and 30 minutes. A minimum of 6 vessels were sam-pled for each Methodology Quantitation was performed with a HewlettPackard/Agilent 1100 series High Performance LiquidChromatograph (HPLC). The method utilizes a Zorbax XDBC18, 5 cm x internal diameter, m particle sizeHPLC column with a mobile phase composed of 38% 25 mMsodium phosphate buffer pH and 62% acetonitrile, a flowrate of mL/min (run time of 2 minutes), a column temper-ature of 35 oC and an injection volume of 10 L.

8 Detection ofboth actives was by UV at a wavelength of 250 and DiscussionMedium SelectionIn selecting a medium for Dissolution testing ofCompound A/B, the solubility characteristics of the indi-vidual active ingredients must be considered. Active A isfreely soluble in water (>140 mg/ml solubility). However,equilibrium solubility measurements are increasing concentration in solution, Active A initial-ly forms micelles, then larger organized structures andfinally a gelatin-like mass that exhibits some of the prop-erties of liquid crystals. Active A s solubility is dependenton its surface-active properties and its ability to self-asso-ciate in concentrated solutions. However, in dilute aque-ous solutions, typical of concentrations found in dissolu-tion procedures , self-association is less likely and theactive precipitates from solution as the free acid.

9 Both pHand ionic strength affect its solubility. The native pH of a1% solution of Active A is approximately The free acidprecipitates when pH is less than B is a crystalline hydrophobic compound withpractically no aqueous solubility ( mg/mL). Its solu-bility increases at low pH to mg/ml in HCl, due tothe formation of the protonated base. It has a solubility mg/ml in NaOH. The addition of surfactantsincreases the aqueous solubility to mg/ml in SDS,a 600-fold increase relative to that in water. In 1% SDS, theequilibrium solubility of Active B is choice of Dissolution medium to accommodateboth active compounds is limited. According to the USP, Dissolution medium may be water, a buffered aqueoussolution (typically pH 4 to 8) or a dilute acid ( to ). Surfactants and electrolytes may also be added toaid in the solubilization of the active ingredient(s).

10 Screening of the following media was carried out usingUSP Apparatus II at 50 rpm and 37 C: (a) water; (b) USPbuffer pH ; (c) USP buffer pH ; (d) USP buffer pH ;(e) N HCl and (f ) SDS in water. The results of thisscreening are shown in Figure A is almost insoluble in the 3 USP buffers, and water. Active B has very low solubility in waterand the 3 USP buffers. In HCl, Active B is more solu-ble, but only SDS provides adequate solubility forboth active and Paddle Speed SelectionThe apparatus and rotational speed selected must pro-vide adequate mixing to disperse the drug product in themedia and to provide a homogeneous mixture for sam-pling, while maintaining the discriminatory power of thedissolution Apparatus II was chosen due to its acceptance as astandard procedure for tablet formulations.