Who we are? Dissolution testing of modified release forms. Dissolution testing of immediate/ modified release forms

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1 Dissolution testing of modified release forms Mumbai , May 3 Samir Haddouchi samir.haddouchi@sps-pharma.com 1 Dissolution testing of immediate/ modified release forms Mumbai , May 3 Samir Haddouchi samir.haddouchi@sps-pharma.com 2 Who we are? CRO specialized in in vitro dissolution and release testing Created in 2005 Located in Orleans (France) Clients in Europe, America, Asia Creation of a knowledge network for the benefit of disso users "Developing dissolution": Academia collaborations 3 1

Outline Introduction Method development: one approach and various tools Case studies Conclusion 4 Biopharmaceutical Classification System (1) 5 BCS (2)

2 Outline Introduction Method development: one approach and various tools Case studies Conclusion 4 Biopharmaceutical Classification System (1) 5 BCS (2) CLASS SOLUBILITY PERMEABILITY LIMITING FACTOR I HIGH HIGH GASTRIC EMPTYING II LOW HIGH DISSOLUTION III HIGH LOW PERMEABILITY IV LOW LOW CASE BY CASE 6 2

3 i.v. Distribution Elimination p.o. solution Absorption Distribution Elimination p.o. IR forms Disintegration? Release? Dissolution Absorption Distribution Elimination p.o. ER forms Release Dissolution Absorption Distribution Elimination BIOPHARMACEUTICAL PHASE PERMEABILITY From JM Cardot, Université d'auvergne, Clermont Ferrand 7 Formulated drug k d Solubilized drug k p Absorbed drug k d = dissolution rate (solubility, including food and formulation) k p = permeability rate (API molecular structure) 8 Disintegration cohesive properties of the formulation Release type and proportion of excipients Dissolution of the drug API characteristics Importance of all steps in dissolution test interpretation Formulation Disintegration Release Dissolution Solubilized Drug 9 3

temperature, humidity, etc IVIVC: Contains dissolution test conditions which may reflect the physiological conditions and simulate in vivo

4 Outline Introduction Method development: one approach and various tools Case studies Conclusion 10 What is my objective? Development: Able to discriminate between various formulations, to help understanding the release mechanism and predict relevant changes due to temperature, humidity, etc IVIVC: Contains dissolution test conditions which may reflect the physiological conditions and simulate in vivo interactions in order to predict in vivo performance. QC control: To ensure batch-to-batch consistency through control of Critical Manufacturing Variables (CMVs) 11 We use only models

5 ph triggered release Preprandial = fasted state ph and residence times in various segments of the GI tract Segment ph MRT (tablets) 1 Dissolution Method Design: stomach 1.8 (1-3) 60 min HCl - 1 h duodenum 6.0 (4-7) < 10 min upper jejunum 6.5 (5.5-7) 30 min ph 6.0-1h lower jejunum 6.8 (6-7.2) 30 min upper ileum 7.2 ( ) 60 min lower ileum 7.5 (7-8) 120 min ph 7.0-2h proximal colon hours 1 non-disintegrating tablets References: 1. ph and mean residence time in various segments of the of fasted GI tract: (Source J.B. Dressman et al., University Frankfurt 2005) 2. Slide from E. Scheubel, Roche Basel: Automated dissolution enteric coating 13 QC methods Glyburide: 0.05M Borate buffer ph 9.5 Atovaquone: 40% Isopropanol in Phosphate buffer ph N NaOH Rufinamide: HCl 0.1N during 1 hour then ph 6.8 until 20 hours 14 Dissolution media selection Composition (ph, etc...) driven by method design. If poorly soluble in aqueous solvents, use of surfactants. Ensure sink condition (Cmax at 30% of solubility) Stability of active ingredient 15 5

6 ph in GI tract Fasted Fed Stomach [1,4-2,1] [1,3-5,4] Duodenum [4,4-6,4] [4,2-6,4] Jejunum [4,4-6,6] [5,2-6,2] Ileon [6,5-7,4] [6,8-7,5] Colon 6,4-7,5 Other routes of administration induce other physiological conditions: - parenteral - rectal - etc 16 Surfactant evaluation Step 1 : Dissolution media (effect of ph) Determine solubility of drug in standard aqueous solutions (0.1N HCl, acetate buffer ph 4.5 and phosphate buffer ph 6.8) Step 2 : Surfactant selection Test one surfactant of each type (cationic, anionic and non-ionic) using the selected aqueous medium and a defined concentration. Step 3 : Determination of surfactant concentration Adjust the surfactant concentration using the minimal quantity. 17 Dissolution volume Should be driven by Solubility of the API in the selected medium Dosage strength of the dosage form LOQ (limit of quantification) of the analytical technique Take care to the range of linearity of the analytical method (± 20% of the range according to ICH) If possible, select UV online measurement 18 6

7 Dissolution apparatus Should be driven by Type of dosage forms: monolithic, multi-particulate, powder, suspension, etc Method design for IR vs ER (ph changes, etc ) Volume needed 19 Agitation rate To develop a maximum discriminating method, agitation should comply to standard guidelines or needs to be tested Apparatus 1 Apparatus 2 Apparatus 3 Apparatus 4 75 to 100 rpm 50 to 75 rpm dpm (Gastric) 20 dpm or less (Intestinal) 4 to 35 ml/min (typical 8; 16; 24) 20 Degassing Dissolved gases can cause variability or changes to the results in various ways. By default, it is recommended to degas the medium prior to testing using: Heat to 41 C, filter under vacuum and dispense gently to the vessel Helium sparging Sonication under vacuum Combination of multiple degassing techniques Otherwise, validate that there is no effect. 21 7

It is important to evaluate filters early

material Nylon Teflon PVDF Glass filters

Discriminating method Visual observation

8 Filtration A potential important source of error. It is important to evaluate filters early in development. Different pore sizes (based on API particle size) Different types of filter material Nylon Teflon PVDF Glass filters 22 Sinkers O-Ring Stainless steel 23 Discriminating method Visual observation is of importance! Artefacts: coning, cross-linking, etc... Make sure the profile is reflecting product quality. 24 8

9 Outline Introduction Method development: one approach and various tools Case studies Conclusion 25 Disintegration cohesive properties of the formulation Release type and proportion of excipients Dissolution of the drug API characteristics Importance of all steps in dissolution test interpretation Formulation Disintegration Release Dissolution Solubilized Drug 26 Disintegration testing: In or out of specifications is not enough: exact measurement Powder dissolution: Sprinkle method: Paddle Hard gelatin capsule of pure API: Basket or Paddle Intrinsic dissolution Apparent dissolution 27 9

the dissolution medium are held constant.

10 Intrinsic dissolution (1) The intrinsic dissolution rate is the rate of dissolution of pure pharmaceutical ingredients when conditions such as surface area, agitation or stirring speed, ph and ionic strength of the dissolution medium are held constant. Determination of the constant k dw D Use of a tablet of pure drug = S(C C ) dt Expressed as mg/min/cm h sat t 2 28 Intrinsic dissolution (2) 29 Intrinsic dissolution (3) 30 10

11 Intrinsic dissolution (4) 31 Intrinsic dissolution (5) 32 Intrinsic dissolution (6) Quantité dissoute (mg/cm2) y = 0.275x R 2 = Temps (min) 33 11

12 Intrinsic dissolution: comparison Quantité dissoute (mg/cm2) Temps (min) 34 Apparent dissolution (1) Dissolution studies when applied to powders enables : The optimization of formulation variables, including particle size The comparison of two batches of an active ingredient having different specific surface areas and particle size distributions. The comparison of biopharmaceutical properties of various polymorphous forms of drug substances can have identical or very different biopharmaceutical properties. 35 Apparent dissolution (2) Eur. Ph

Powder 0.16 88.45 Capsule grade 0.53 394.4 Crystal grade 0.33 58.

13 Apparent dissolution (3) 37 Case study Powder dissolution : Acetaminophen Surface area and particle size Product Surface area m 2 /g Mean diameter µm Powder Capsule grade Crystal grade Fine powder Micronized Microcaps Acetaminophen powder 39 13

8 Mean of three determinations Product K h -1 Powder 1.

14 Acetaminophen Micronized 40 Acetaminophen microcaps 41 Intrinsic dissolution rate Amount 100 mg ph 5.8 Mean of three determinations Product K h -1 Powder 1.8 Capsule grade 1.7 Crystal grade 1.8 Fine powder 1.8 Micronized 1.8 Microcaps

15 Apparent dissolution % Dissolved Flow- through cell for powder Closed system ph 5.8 Flow rate 16 ml/min Amount 100 mg Six determinations Time (min) Powder Micronized Capsule grade Superfine powder Crystal grade Microcaps 43 Various tools These activities may be considered as time consuming but - In vitro testing is not expensive compared to in vivo studies. - It can facilitate formulation development - These are good tools to derisk biostudies Different approaches can be used: - Rx, DSC - intrinsic / apparent dissolution - evaluation of different dissolution methods than USP1&2 - use of different phs - use of biorelevant media Finally, development time can be shorten. 44 Outline Introduction Method development: one approach and various tools Case studies Conclusion 45 15

16 Case study: IR tablets Product already marketed Developed more than 20 years ago Class I drug: soluble and good permeation 46 Background A paddle dissolution method is in place and validated for QC purposes. - Paddle 50rpm - 500mL of HCl 0.1N - UV online Changes: - new API supplier - slightly different quantitative formulation Both formulations had been tested with the existing paddle method In vitro equivalence demonstrated 47 Background In vitro comparison using the paddle method Dissolved % Marketed formulation (n=18) New formulation (n=18) Time (min) 48 16

17 Background Based on those data, the bioequivalence study was initiated: - Male and female subjects - 24 healthy volunteers - fasted conditions Results showed in-equivalence between both formulations. 49 Background Marketed formulation New formulation Hypothesis API? - Intrinsic dissolution rate - Apparent dissolution Formulation? - Change the dissolution medium - Change the dissolution technique Manufacturing process? - Evaluate the product at each step of the process 51 17

18 APIs investigations No polymorph (or pseudo-polymorph) known for this drug no need to go for intrinsic dissolution rate. Apparent dissolution using USP4 flow through cell with the specific powder cell according to EP chapter Starting from the existing paddle method, a USP4 was developed using a closed system with the same dissolution medium and the same UV quantification method. 52 APIs investigations Phase 1a (n=6) Phase 1b (n=6) Phase 2 (n=6) API investigations: conclusion No difference showed by this technique between both APIs. Remaining options: Formulation or manufacturing process 54 18

19 Formulation and process Apply the USP4 flow through cell method to evaluate its discriminative ability - on the finished products (formulation) - on samples taken at each process steps (process) Conditions identical to previously except that the cell is adapted to the tested form (tablet or powder cells). 55 Tablets Marketed product New formulation Background The rank obtained is identical to the rank observed in vivo. Marketed formulation New formulation

20 IR tablets case study The flow through cell dissolution technique was able to show the difference seen in vivo with the same rank order. This dissolution method was used to support a reformulation of the product. A new formulation was tested with both dissolution methods which showed it to be equivalent in vitro. Even tough there was no certainty about an IVIVC or IVIVR, using USP4 was a way to minimize the risk of bio in equivalence. The BE study was repeated and concluded favorably. The paddle method was maintained as QC method for the release of batches. And the USP4 method was kept in house as a tool for R&D. 58 CR suspension case study Deficiency letter from US authorities 59 Background and strategy Injectable suspension containing two Active Ingredients Following the request of US FDA, a development strategy has been built to ensure answering all questions - Evaluation of the test conditions - Trials with both equipments - Optimization of the selected method

Preliminary work A solubility study has been carried out at ph values close to physiological conditions Defined medium was phosphate buffer ph 7.

21 Preliminary work A solubility study has been carried out at ph values close to physiological conditions Defined medium was phosphate buffer ph Tween Filter selection has been carried out to satisfy: - No drug adsorption - Adapted pore size - No leachables from the filters. 61 USP2 dissolution test Trial using USP2: 500ml at 25 rpm Closed loop system Fraction collection Cell UV-Visible photometer Magnetic stirrer Pump 63 21

22 USP4 dissolution test Trial using USP4: 500ml at 8ml/min USP Apparatus Dissolution testing or release testing? Better product understanding Trial using USP4: 500ml at 8ml/min USP Apparatus Conclusion (2) Recently, the authorities published clear statements requiring dissolution data for suspension formulations such as: Betamethasone Acetate/Betamethasone Sodium Phosphate Leuprolide Acetate Methylprednisolone Acetate Risperidone Triamcinolone Acetonide Naltrexone Octreotide injection " Develop a dissolution method using USP IV (Flow-Through Cell), and, if applicable, Apparatus II (Paddle) or any other appropriate method, for comparative evaluation by the Agency" Source:(US FDA website) 66 22

23 Take-home messages Complicated media or non standard dissolution techniques may be used but with proper justification only when the compendial methods failed. Make sure the profile is showing what is of interest for you. Be science-driven and not tradition-driven Search the best simple method that answers your needs. 67 Thank you for your attention! Questions? 68 23

29-Apr Outline. Automation in dissolution testing. Mumbai , May 4 Samir Haddouchi

29-Apr Outline. Automation in dissolution testing. Mumbai , May 4 Samir Haddouchi Automation in dissolution testing Mumbai - 2013, May 4 Samir Haddouchi samir.haddouchi@sps-pharma.com 1 Outline - Introduction about automation - Automation for dissolution testing - Validation of automated