CuttingEdge | Celdbrating 13" yar of publication Se Group Leader ‘Analytical Development Dept Baroque Pharmaceuticals Pvt.Ltd, a STITT UT ear Shah of Oral Solid Dosage Formulations ‘Anand, Gujarat Spinco Biotech CuttingEdge This article covers the major overview points shared by the author during ‘The Future of Bio/Pharmaceutical Analysis Online Summit” ‘was held on 28-29 June 2023 by European Pharmaceutical Review journal which was published by Russell Publishing Ltd, UK. Following are the key points covered: + Dissolution testing of oral solid dosage forms is @ complex procedure with a range of different equipment setups. Learn how to select the optimal method for QC testing of ‘OSD formulations and explore common issues that lead to test failures. + Explore dissolution method development for oral dng products, including ‘conventional release, prolonged release and delayed release formulations + Dissolution techniques for capsule dosage form with cross-linking + Benefit from practical advice on dissolution testing, including how to assess the risks of using automation, how to ensure effective filter selection and more. + Stay up-to-date withthe latest on dissolution testing, as well as changes to European and US Pharmacopeia What is Dissolution? Dissolution tests determine the rate and extent of release of the drug substance from 1 drug product under specific vonditions and specific times. Dissolution tests help in evaluating bioavailability of drug substances and are part of release criteria during quality control testing. Dissolution tests are also undertaken during product development to study bateh-to-batch consistency, evaluate stability ofthe product and also for assuring compliance to regulations. Regulatory agencies use the dissolution test to provide a quality connection from a pivotal bio batch to the commercialized product. For this reason, the dissolution test development and validation are critical factors in insuring that the tes is robust and clinically relevant. September 2023,What is Dissolution Process? + Initial mechanical lag + Wetting + Penetration + Disintegration + Disaggregation + Dissolution + Release Absorption of drug in systemic circulation from dosage form after dissolution The dissolution test is a globally required test for most of all pharmaceutical products that are ‘not true solutions. Dissolution or in vitro release of the drug sustanee fom the product into a {ypically aqueous-based “medium is linked to the release of the drug into the body, making it available for absorption, and then efficacy or clinical outcome. Clinical relevance comes from developing a test that provides understanding of the product release mechanism and an in vivo in vitro correlation (IVIVC). The acceptance criteria in the drug product (DP) specification or September 2023 Dissolution Testing compendial monograph attributed to a clinically relevant test are most important and useful, Disintegration of dosage forms and absorption in systemic circulation are critical step to achieve efficacy. (Figure 3) Different types of Oral Solid Formulations (Figure 4) + Tablets + Capsules + Granules + Powder + PillsLozenges *+ Oral Strips ete Dissolution method development Dissolution method development and validation require a good understanding of the theory of dissolution and the roles of the key parameters of the dissofution test, A complete dissolution package would consider at a minimum the dissolution apparatus used, equipment qualification with analytical methods like requirements as_per appropriate regulatory. guidelines. Performing Fig. 2 Disolution Process dissolution is one part that should be developed while analysis of dissolution aliquots is other part which represents results in terms of release. Dissolution development and validation are well described by USP general chapter <1092>, The Dissolution Procedure: Development and Validation and ICH Q2(R1) Validation of analytical procedures, Dissolution method development is divided in 2 Parts 1) Dissolution Media, Apparatus & Parameters selection 2) Analytical method development! selection -by UV ~by HPLCIUPLE Points to be considered during method development of Dissolution Drug substance solubility profile (As per BCS Classification) ‘Sink condition (For Volume ) Selection of in vitro dissolution? release mediumm/media Selection of an appropriate apparatus. Spinco Biotech Cutting EdgeDissolution Testing Fig. 3: Drug abiorption process Selection of an appropriate rotation speed (RPM). + Selection of an appropriate time points for release. + Automation and Filtration study + Justification and data to support selection of surfactant type and concentration. (up to 2%6) * Dissolution in different pH media of physiological range, + (For Bg,, pH 1.2, 4.5, 68, 7.5) ‘without and with surfactant. The Ideal Dissolution Medium Should be between physiological pH range 1.2 to 18 + Should Meets Sink condition + Should simple in preparation + Drug should be stable up to 24 Hrs in media. + Should be compatible with Surfactant and/or Alcohol + Should be compatible with filter Water is used as a medium with caution because... *+ No buffer capacity * Quality differs with source change * Quality differs with Water System, filters ete., + pH and conduct monitor + Milli Q water is @ good option ty should be issolution of OSD formulation: Capsule dissolution As is the case with other oral sotid dosage forms, USP Apparatus (basket), USP Apparatus 2 (paddles), USP Apparatus 5 (reciprocating cylinder), and USP Apparatus 4 (flow-through cell) are most often chosen as the dissolution apparatus for capsules. Generally, Basket or Paddle with/without sinkers are preferred. However, several specific benefits and drawbacks must be considered inselecting and using the dissol apparatus for capsules:~ Capsules may be filled with a material that has a specific gravity less than that of water. So, the capsules may float in an aqueous dissolution medium. Instead of dissolving completely during the dissolution test, the capsule shell may soften and disintegrate into a sticky or waxy mass that ean adhere t9 any point in the dissolution vessel and in different areas in different vessels, generating high variability in the results ‘The capsule fill material may form a film on the surface ofthe dissolution medium during the course of the test The capsule dissolution process involves three stages: (1) Rupture of the capsule shell (2) Release and dispersion of the with detail of eross-inking issue USP general chapter <1094> Capsule-Dissolution Testing and BPE Spinco Biorech CuttingEdge Fig- 7: Crosslinked gelatin capsule n USP apparatus 1 — Basket Related Quality Attributes has described in depth for Capsule cross-linking Use of enzymes are depend on pH of dissolution media, for example Dissolution Medium with pH 340 A quantity of Pepsin that results in an activity of not more than 7,50,000. units/L. of dissolution medium is used. Dissolution Medium with pH >4.0 and <6.8 A quantity of Papain that results in anactivity of not more than 5,50,000 units/L of dissolution medium or a ‘quantity of Bromelain that results ity of not more than 30 ¢gelatin-digesting units (GDUY/L of dissolution medium are used Dissolution Medium with pH 268 A quantity of Panereatin that results in a protease activity of not more than 2000 units/l. of dissolution medium is used. Note: Tests to be carryout to ensure that selected enzymes do not adversely interact with formulation For Example, Dissolution media is 0.1 N HCL with Pepsin Dissolution media is water with Papain Dissolution media is pH 68 phosphate buffer with Pancreatin Challenges for Tier two concept - Option 1 Selection of enzyme Optimization of enzyme concentration Filter interference study Precision Recovery Linearity Solution stability To verify that Tier 2 dissolution do not affect the dissolution profile when compare with Tier | test Qualifying / Setting chromatography Use of Enzymes: Tier two concept - Option 2 Dissolution medium conta Surfactants which denature the enzyme activity If the dissolution medium contains surfactant or other ingredients that are known to denature the used enzyme activity, a Pre-treatment step in the dissolution testing of the dosage form may be applied. ‘The Pre-treatment step If the dissolution medium contains surfactants, a Pre-treatment for the cross-linked gelatin capsules done with the medium containing the enzyme (As per pH! of media) in the absent of surfactant. September 2023,Dissolution Testing ‘This Pre-treatinent consists of adding the enzyme to the specified medium without the surfactant and running the agitation for a short period of time, in most cases not more than 15 min, (called as contact time or Incubation time) ‘After this period, a solution ‘containing the surfactant is added to the dissolution vessel in such a way that the final concentration of the surfactant in the vessel will be same as QC release media. ‘The Pre-treatment time is included in the total run time of the dissolution method. + OGD Media (QC release media) is 0.05 M Na Phosphate buffer pH 75 with 2% wiv SLS + While Tier 2 media is. Pre-treatment step = 0.05M_Na phosphate buffer pH 7.5 : 700 mL with 1% Pancreatin Here, as per pH 7.5 of media, Panereatin is selected for dissolution, Concentration of enzyme decide by optimization trial during development. 900 mL. is_dissolution media volume but 700 mL is decided based on optimization tral during development. + After 15 Min (Contact time) Add 200 mL of pH 7.5 Phosphate buffer with 9% SLS. Here, 9% SLS added to make concentration of SLS in vessel September 2023 2% as per QC media So, Final concentration is same for SLS. After another 30 min (15 Min contact time + 30 Min running time = 45 Min which is Q Point) sampling done for release testing, + Other Examples are. Celecoxib Capsule Enzalutamide Capsule ete. Challenges for Tier two concept - Option 2 + Selection of enzyme + Optimization of enzyme concentration + Composition and Optimization of volume required for Pre-treatment + Contact time optimization (incubation time) + Filter interference study + Precision + Recovery nearity Solution stability + To verify that Tier 2 dissolution do not affect the dissolution profile when compare with Tier 1 test + Qualifying / Setting chromatography Conclusion Dissolution testing is primarily used in the pharmaceutical industry as quality control tool to monitor the formulation and manufacturing processes of the dosage form. Dissolution is considered by most -gulatory agencies as a highly critical quality characteristic for most solid dosage forms. Dissolution media selection is very critical matter and depends fon inherent property of active ingredient and respective dosage form, Different Dissolution USP apparatus are used forall Solid oral dosage forms as per suitability of dosage form in terms of release. Suitable RPM as per decided dissolution apparatus and time interval (Withdrawal points) are set to achieve dissolution release. For capsule which has shell made up. of gelatin, cross-linking. is major issue. Sometimes batch fails in stability study due to crossclinking, In this condition conelition, enzymes are best option for achieving Q point release as per specification. This Tier 2 activity is used for gelatin capsule shell used for hard & soft gelatin capsule as well as gelatin coated tablets dissolution queries In Tier 2 option, enzymes are used as per pH of respective QC media with proper optimization, In option 1, it is easy to explain media composition and procedure while for option 2, It is difficult to explain, Pre- treatment step and incubation time should be optimize with caution and finalize. Using Tier 2 Option 1 and 2, we can save dissolution and ultimately by regulatory justification with efficient data, file the product, References. inte Spinco Biotech Rm Cutting Edge