Development Of A USP Apparatus 3 Dissolution Method For .
Development of a USP Apparatus 3 Dissolution Method forProgesterone Soft Gelatin Capsules.D. Monterroza, L. Ponce De LeónOBJECTIVEThe overall aim of this project was to develop and validate a discriminating dissolutionmethod for an oily suspension of progesterone contained in soft gelatin capsules, achievingNLT 85% dissolved at NMT 90 minutes.BACKGROUNDSoft capsules (mainly made with gelatin) are becoming more popular in recent years.Advantages of this dosage form include: t mask unpleasant odors and flavors, possibility ofencapsulating oil or semisolids materials and prevention of counterfeiting, among others.However, the main advantage of this dosage form is the possibility to overcomebioavailability issues for BCS class compounds II and IV mainly, since differentformulation approaches (like direct solubilization by co-solvency or pH adjustments andalso suspension of a micronized drug substance in a liquid vehicle) can be used, which arenot feasible using other dosage forms like tablets or hard gelatin capsules with powders.For soft capsules, as for other solid dosage forms, transdermal patches, stents and oralsuspensions; a dissolution test is required not just to formulation design but to assessproduct quality. What is unique of a well-designed dissolution test, is that is the onlyfinished product test method in routine use that measures the effect of the formulation andphysical properties of the active pharmaceutical ingredient (API) on the in vitro rate of drugsolubilization. As a result, dissolution testing is the only test that monitors the impact ofenvironmental storage conditions and manufacturing process upon the rate of drug releaseform the dosage form. These sensitivities have led to use the dissolution test as a measureof formulation bioperformance.Developing a dissolution test for a soft capsule containing a hydrophilic content follows thesame approach that we can follow for the development of a similar method for a tablet or ahard capsule containing powders, using USP dissolution apparatus 1 or 2 (baskets orpaddles, respectively). However, for soft capsules containing oily based solutions orsuspensions of one or more APIs, using the same apparatus can lead into some challenges;during dissolution, the oil may form a layer above the aqueous the aqueous medium and oildroplets can be suspended in the medium which can lead into sampling problems.Additionally, the existence of a lipid phase may hinder the release of the drug.In this project we evaluate using USP dissolution apparatus 3 (reciprocating cylinder) as analternative to be used for developing and validate reliable dissolution methods for oilformulations contained in soft capsules. We focused on an oily suspension of micronizedprogesterone (PRO) but a similar approach could be used for oily solutions of one or moreAPIs.1
Development of a USP Apparatus 3 Dissolution Method forProgesterone Soft Gelatin Capsules.D. Monterroza, L. Ponce De LeónMETHODOLOGYSink Condition StudiesThe saturation solubility of PRO was measured in the following solvents: water; simulatedgastric fluid (SGF); pH 4.5 acetate, and pH 6.8 phosphate buffers. Each solvent wasevaluated with 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, and 4% (w/v) of sodium lauryl sulfate (SLS).Additionally, each solvent was evaluated with 0.1, 0.3, 0.5, 10, 1.5, and 2.0% (w/v) ofpolysorbate 80 (P-80).By duplicate, excess PRO was added to 100-mL of each media in conical flasks andagitated sporadically at 37 C for 10 hours on a recirculating water bath. Each solution waskept aside at room temperature for 8 hours until equilibrium was achieved.The solutions were then filtered through 0.45µm PVDF filters (filter was selected afterprevious experiments), and the filtrate was suitably diluted and quantitated by HPLC(Agilent 1200 with PDA detector) on a Zorbax XDB C18 column (150 x 4.6 mm; 5µm) ata flow rate of 1.0 mL/min, with an analysis time of 9 minutes. PRO was eluted using amobile phase of methanol/water: 20/80 (v/v), and retention time was about 4 minutes. Forall the next experiments, samples were filtered and quantified using the above procedure.Apparatus SelectionDissolution rate of six capsules of Progesterone 100 and 200 mg capsules was evaluatedusing 900 mL of 4.0% SLS in water as a dissolution media, in USP dissolution apparatus 1and 2 (Distek 6100) at 150 and 100 rpm respectively. Additionally, six capsules of the twoproducts were evaluated using 250 mL of the same media but in the USP dissolutionapparatus 3 (reciprocating cylinder) at 40 dips per minute.The dissolution conditions were selected as the more aggressive but accepted fordissolution methods for each apparatus without additional justification or excessiveturbulence that could affect negatively the results. Dissolution media was selected based onthe sink condition studies.Samples were quantified by HPLC and the results were expressed as percentage ofdissolved progesterone respect to the label.Screening of Conditions Using USP Apparatus 3An experimental design (DOE) of Plackett-Burman was proposed to assess the effect ofdifferent variables on the dissolution results in the Apparatus 3. Dissolution profiles for twolots of Progesterone 100 mg capsules; one of them manufactured with micronized API andthe other manufactured with a material having higher particle size distribution. Thepercentage of difference between the two products was selected as the response for thisDOE.2
Development of a USP Apparatus 3 Dissolution Method forProgesterone Soft Gelatin Capsules.D. Monterroza, L. Ponce De LeónVariables and design of experiment are summarized in Table 1 and Table 2, respectively.Table 1. Evaluated Variables in the Design of ExperimentLevelVariable-1 1WaterpH 6.8 Phosphate BufferA:Dissolution media solventB:% of SLS in the dissolution media3.04.0C:Volume of media (mL)220250D:Top screen (mesh number)*3040E:Apparatus Speed (dips per minute)3040F:Sinkers (8-mesh basket)NOSIG:Media DegassingNOSI*For all experiments, bottom screen was fixed as 40 mesh.Table 2. Design of ExperimentExperimentNo.12345678VariablesABCDEFG-1 1 1-1 1-1-1 1-1-1 1 1-1 1-1 1-1-1-1 1 1-1 1 1 1-1-1-1 1 1-1 1-1 1-1-1-1 1 1 1 1-1 1-1-1-1 1 1 1 1-1 1-1-1-1 1Dissolution Method EvaluationIn order to evaluate if the dissolution method could discriminate products with significantmodification in formulations, four different lots of Progesterone 100 mg with differences inparticle size and level of lecithin in the formulation, were manufactured.Formulations are shown in Table 3. It should be clarified that because confidential reasons,neither particle size nor actual level of lecithin are provided.3
Development of a USP Apparatus 3 Dissolution Method forProgesterone Soft Gelatin Capsules.D. Monterroza, L. Ponce De LeónTable 3.Product No.APIParticle Size Distribution*Level of lledHigh* NOTE: Micronized provides a lower particle size distribution than Milled API.12 capsules of each one of the four products were evaluated and dissolution profiles wereplotted.Development and Validation of the Final Dissolution MethodDissolution method was validated according to USP recommendations in General Chapter 1092 “The Dissolution Procedure: Development and Validation”. The analytical methodwas evaluated for: Specificity, Linearity and Range, Accuracy/Recovery, Precision, and,Standard and Sample Solution Stability.RESULTS AND DISCUSSIONSink Condition StudiesSolubility of PRO using until 2.0% (w/v) of Polysorbate 80 as surfactant, unrelated to thepH of the media, was lower than 0.5 mg/mL. This surfactant was discharged.Solubility results of PRO using until 4.0% of SLS as surfactant are summarized in Table 4.Using the solubility, the sink condition factor “F” at each condition was calculated asfollows:F (So * V) / Dwhere,So:solubility in each media (mg/mL)V:maximum volume for each apparatus. V is 900 mL for Apparatus 1 and 2; and 250mL for Apparatus 3.D:maximum dose strength of the drug product, 200 mg.4
Development of a USP Apparatus 3 Dissolution Method forProgesterone Soft Gelatin Capsules.D. Monterroza, L. Ponce De LeónAccording to literature, an F value of at least 3 (three times the maximum dose strength)guarantees that the dissolution rate of the drug product is independent of the amount of theAPI that is already dissolved in the media, which is desirable for any dissolution method.For Apparatus 1 and 2, where the maximum volume of media is 900 mL, an F value of 3 isreached with about NLT 0.5% of SLS, irrespective of the media pH. For DissolutionApparatus 3, where the maximum volume of media is 250 mL, an F value of 3 is reachedwhen the media contains NLT 2.0% of SLS, irrespective of the media pH.Table 4.Dissolution MediaSolventWaterSimulatedGastric Fluid(pH 1.2)pH 4.5 AcetateBufferpH 6.8Phosphate5% SLS (w/v)So(mean SD)mg/mL“F”, for 250mL“F”, for 3.03.54.00.00.51.01.52.02.53.03.54.00.00.50.10 0.0140.85 0.0711.90 0.0102.40 0.2832.75 0.2122.85 0.0714.00 0.2834.65 0.2124.75 0.2120.10 0.0141.00 0.1412.00 0.2832.15 0.2122.85 0.2122.90 0.1113.90 0.1414.85 0.2135.00 0.1440.10 0.0141.10 0.1101.95 0.0712.45 0.2123.15 0.2122.90 0.0104.30 0.1415.05 0.0714.65 0.02140.35 0.0711.10 5910131318222305911141319232125
Development of a USP Apparatus 3 Dissolution Method forProgesterone Soft Gelatin Capsules.D. Monterroza, L. Ponce De LeónBuffer1.01.52.02.53.03.54.02.45 0.2102.60 0.0113.60 0.2843.70 0.5664.85 0.3545.40 01446.10 0.283335567811121617222427According to this data, aqueous solubility of PRO increases proportionally to theconcentration of SLS in the evaluated range; irrespective of the pH. We decided not tochoose water as the media since it is not recommended by USP and therefore pH 6.8Phosphate Buffer with at least 1.5% of SLS (w/v) was selected as the dissolution media fornext experiments aimed to selecting dissolution apparatus.Apparatus SelectionAt this point, we decided to use the most aggressive condition of Apparatus 1, 2 and 3 asfollows:Apparatus 1 (basket): with 900 mL of dissolution media, at 150 rpm.Apparatus 2 (paddles): with 900 mL of dissolution media, at 100 rpmApparatus 3 (reciprocating cylinder): with 250 mL of dissolution media, at 40 dips/minute.Initial experiments using between 0.5% and 2% of SLS, were unable to reach at 85% ofdissolution in not more than 90 minutes. Therefore, we probed the above mentioneddissolution conditions for each apparatus, using 4.0% of SLS, which was the maximumconcentration evaluated during the solubility studies.Dissolution profile obtained using Apparatus 1 and 2 are shown in Figure 1.Figure 1. Dissolution profile of Progesterone 200 mg, using 900 mL of pH 6.8phosphate buffer containing 4.0% of SLS, at 150 rpm (apparatus 1) and at 100 rpm(apparatus 2).6
Development of a USP Apparatus 3 Dissolution Method forProgesterone Soft Gelatin Capsules.D. Monterroza, L. Ponce De LeónWe could see from these results that even using 4.0% of SLS, which is too much higherthan the minimum concentration that provide sink conditions for 900 mL of media (about1.0% of SLS), the objective of reach not less than 85% of dissolution in not more than 90minutes, is not accomplished. It is noted that these results are not in disagreement with thesink condition experiments already mentioned; since the final dissolution rate is relatedmainly to the drug product even when the dissolution media has enough solubility todissolved at least three timed the maximum amount of the API per unit (F 3).Based on the previous results, for Apparatus 3, it was decided to evaluate from 1.0% to4.0% percent of SLS. Results are shown in Figure 2.Figure 2. Dissolution profile of Progesterone 200 mg, using 250 mL of pH 6.8phosphate buffer containing either 1.0%, 2.0% 3.0% and 4.0% of SLS, at 40 dips perminute.7
Development of a USP Apparatus 3 Dissolution Method forProgesterone Soft Gelatin Capsules.D. Monterroza, L. Ponce De LeónResults using apparatus 3 were really promising, since more than 85% of dissolution wasreached when between 3.0% and 4.0% of SLS was added to the dissolution media. Apossible explanation for these results is that apparatus 3 provides a high turbulence thatmay be useful with dosage forms such as liquid-filled capsules with lipophilic filling,compared to the apparatus 1 or 2.Screening of Conditions Using USP Apparatus 3Modifying different variables of the apparatus 3, a DOE was proposed, in order to evaluatethe effect of those variables on the discriminating capabilities of the dissolution method.(see Table 1 and Table 2.)Results are shown in Table 5.8
Development of a USP Apparatus 3 Dissolution Method forProgesterone Soft Gelatin Capsules.D. Monterroza, L. Ponce De LeónTable 5.ExperimentNo.Solvent% of SLSMediaVolume(mL)1Agua322040302Buffer pH 6.83220303Buffer pH 6.842204Agua45Buffer pH 6.86TopDips perSinkersScreen MinuteDegassing% uffer pH 6.842504040SISI11After statistical evaluation, it was concluded that the parameters of the dissolution methodthat more affected the discriminating capabilities of the method were: presence of sinkersand % of SLS in the dissolution media.Final method conditions were established as follows:Apparatus:Dissolution Media:Speed:Top Screen:Bottom Screen:Sinkers:3 (reciprocating cylinder)250 mL of 4.0% of SLS in pH 6.8 Phosphate Buffer30 dips per minute30 mesh40 meshYes, (8-mesh basket)Dissolution Method EvaluationDissolution profiles of the four different products, with differences in particle size (microhas lower particle size than milled) and level of lecithin in the formulation, are shown inFigure 3.It is noted than the dissolution method can differentiate between particle size and also,especially in the case of milled progesterone, shows differences in dissolution rate betweenproducts with differences in the level of lecithin.It is interesting to see that the product with lower particle size shows a lower dissolutionrate. We could establish that this is due to suspension with lower particle size, has asignificant higher viscosity and its dispersion in the dissolution media is lower than the9
Development of a USP Apparatus 3 Dissolution Method forProgesterone Soft Gelatin Capsules.D. Monterroza, L. Ponce De Leónsuspension with milled progesterone which flows and disperse easier. Level of lecithin alsoaffects, since lecithin increases the flow properties and therefore dispersion of thesuspension, at least in the evaluated range.Figure 3. Dissolution profiles using the proposed dissolution method on 4 productsdiffering in particle size distribution/level of lecithin in the formulation.CONCLUSIONS AND FUTURE PROSPECTSWe have developed and validated a dissolution method for a soft gelatin capsule containingan oily base formulation. It has been proven the use of USP dissolution apparatus 3 for thispurpose, showing significant benefits compare to the traditional and more commonly usedapparatus 1 (baskets) and 2 (paddles).10
Development and Validation of the Final Dissolution Method Dissolution method was validated according to USP recommendations in General Chapter 1092 “The Dissolution Procedure: Development and Validation”. The analytical method was evaluated for: Specificity, Linearity and Range, Accuracy/Recovery, Precision, and,
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