Dissolution Tools for API Characterization.

Dissolution Tools for API Characterization. Tablet Compression Workshop 25-26 January 2017 Department of Organic Technology, UTC Iva Martincová iva.martincova@sotax.com Petr Zámostný petr.zamostny@vscht.cz Samir Haddouchi samir.haddouchi@sps-pharma.com

SOTAX Group SPS Pharma Services CRO offering all analytical services (founded in 2005) The only company in the world specialized in R&D for dissolution and release testing Located in Orleans, France Facility fully cgmp-compliant, US FDA-inspected, regularly subject to audits Key Portfolio: R&D Services Routine Analytical Services (GMP) Support Services 2

SOTAX Group Privately owned, independent, globally active Corporate headquarter in Switzerland with a strong presence in Asia and the America Direct sales channels / own subsidiaries with distributor channel SPS Pharma 2005 Zymark 2008 Pharma Dr. Schleuniger - 2013 Since 1973.

Dissolution Tools for API Characterization. Introduction on Dissolution API Characterization Intrinsic Dissolution Rate Apparent Dissolution Case Studies: Paracetamol Case Studies: IR Tablets Conclusion 4

Plasma Concentration Introduction on Dissolution. Distribution Elimination Dosage form API released API dissolved API absorbed API in blood Efficacy Safety API in tissues Release Absorption C max Distribution AUC Metabolisation Elimination Effect Adapted from Prof. Cardot & Prof. Beyssac (Université d Auvergne) T max Time 5

Introduction on Dissolution. dw dt D h S(C s C b) dw/dt D h S C s C b = dissolution rate = diffusion coefficient = thickness of the stagnant layer surrounding the dissolving particle = the surface area of the solid = the concentration of a saturated solution = the concentration at any given time of the bulk solution 6

Introduction on Dissolution USP 1, 2,4 USP 1: Rotating Basket Temperature inside the vessel at 37 ± 0.5 C Shaft with a cylindrical basket Problem with homogeneity of mixing Difficulty to monitor the dosage form Problem of corrosion Problem of polymers/gelatin and mesh Bubbles on the mesh (degassing) Cleaning process may be tedious Sensitivity to environmental conditions 7

Introduction on Dissolution USP 1, 2, 4 USP 2: Rotating Paddle Temperature inside the vessel at 37 ± 0.5 C Shaft with a paddle placed at 25 mm from bottom Problem with light formulation Use of sinkers Insoluble excipients Coning effect Sensitivity to environmental conditions 8

Introduction on Dissolution USP 1, 2, 4 USP 4: Flow-Through Cell Flexibility: from very small volumes to infinite Monitoring the release and not the dissolution properties Allowing control of the dosage form positioning No sensitivity to environmental conditions 9

CHALLENGE DOSAGE FORM USP 4 - Dosage Form Challenges MR, CR, SR and ER tablets API s Powders Granules Capsules Pellets Medical devices Drug-eluting beads & stents Implants Coated ocular implants & lenses Suppositories Soft-gelatin capsules Parenterals Emulsions Suspensions Microspheres Semi-solids ph change Poorly soluble Low dose Hydrodynamic control Floating Capsule interference Low dose Lipid interference Low dose Small particles Dialysis often required

USP 4 - Specific cells for all dosage forms small tablets large tablets different adapters for semi-solids, contact lenses, dialysis bags, etc. powder suppositories implants large stents small stents or products with adsorption problems

Introduction on Dissolution. Importance of all steps in a dissolution test interpretation Disintegration Release Dissolution of the drug cohesive properties of the formulation type and proportion of excipients API characteristics Dosage Form Release Disintegration Dissolution Dissolved Drug 12

Dissolution Tools for API Characterization. Introduction on Dissolution API Characterization Intrinsic Dissolution Rate Apparent Dissolution Case Studies: Paracetamol Case Studies: IR Tablets Conclusion 13

Intrinsic Dissolution. (1) The intrinsic dissolution rate is the rate of dissolution of pure pharmaceutical ingredients when conditions such as volume, agitation, ph and ionic strength of the dissolution medium and surface area are held constant. Physical properties effects are minimized or eliminated. Determination of the constant k Use of a tablet of pure drug Expressed as mg/min/cm 2 dw dt D h S(C sat C t) Eur. Ph. 2.9.29 USP <1087> 14

Intrinsic Dissolution. (2) 15

Intrinsic Dissolution. (3) 16

Intrinsic Dissolution. (4) 17

Amount dissolved (mg/cm 2 ) Intrinsic Dissolution. (5) 20 18 16 14 12 10 8 y = 0.275x - 0.2133 R² = 0.9998 6 4 2 0 0 10 20 30 40 50 60 Time (min) 18

Amount dissolved (mg/cm 2 ) Intrinsic Dissolution: Comparison. 25 20 15 10 5 0 0 10 20 30 40 50 60 70 80 90 Time (min) 19

Dissolution Tools for API Characterization. Introduction on Dissolution API Characterization Intrinsic Dissolution Rate Apparent Dissolution Case Studies: Paracetamol Case Studies: IR Tablets Conclusion 20

Apparent Dissolution. (1) When applied to powders, dissolution studies allow: To optimize formulation variables, including particle size. To compare batches of active ingredient having different physical properties: Surface area and particle size distribution. The comparison of various polymorphic forms of drug substances can show identical or very different biopharmaceutical properties. 21

The Flow-Through Cell. The test sample is located in a small volume cell through which solvent passes The eluate is filtered upon leaving the cell The eluate is analyzed directly (on-line) with a spectrophotometer and/or collected in a fraction collector (off-line) 22

Open System with ph Change. Splitter C Cell Waste Fraction Collection differential t Pump Media Selector 23

Closed Loop System. Fraction Collection C Cell Magnetic stirrer UV-Vis Photometer cumulative t Pump 24

Why Choose USP 4? USP 4 is the method of choice for poorly soluble compounds in order to maintain sink conditions USP 4 is a method for low volume dissolution media Specific cells for special / novel dosage forms are available Automated ph changes can be easily achieved for IVIVC studies Solves many challenges of USP 2 such as floating or sticking products, and inherent sampling issues USP 4 method is increasingly used for measuring API characterization (apparent dissolution in Eur. Ph. 2.9.43) USP 4 is a recomended method for injectable suspensions 25

APIs: Apparent Dissolution Powder cell for apparent dissolution can also be used for pellets and granules. Dissolution results depend on physical properties of powder. Advantages: No floating, no sticking Powder / API is not compressed Powder is wet immediately Filter (0.7 µm) Pre-filter (2.7 µm) Fixed sieve (450 µm) Mobile sieve (450 µm) 3-stage filtration Dispersion disk (sieve + blocker) Fixed sieve (450 µm) Filter (2.7 µm) Fixed sieve (450 µm) Sieves + filter to support powder

Apparent Dissolution. (2) Eur. Ph. 2.9.43 27

Apparent Dissolution. (3) 28

Dissolution Tools for API Characterization. Introduction on Dissolution API Characterization Intrinsic Dissolution Rate Apparent Dissolution Case Studies 1: VSCHT Effect of maize starch properties on drug dissolution rate Case Studies 2: VSCHT Doc. Zámostný - Dissolution Rate of Agglomerates, QbD Approach To formulation Conclusion 29

Effect of maize starch properties on drug dissolution rate Case study 1

Aim of the work Pregelatinized maize starch contributes to retardation of both soluble and slightly soluble drugs compared to microcrystalline cellulose or spray-dried lactose Levina M, Rajabi-Siahboomi AR. The influence of excipients on drug release from hydroxypropyl methylcellulose matrices. J Pharm Sci 2004;93:2746-54. Different cross-linking in starch samples causes substantial differences in release Onofre F, Wang Y-J, Mauromoustakos A. Effects of structure and modification on sustained release properties of starches. Carbohydr Polym 2009;76:541-7. Our objective compare API release from different starch matrices describe release rate by mathematical model correlate release parameters to functional properties

Experimental 5 different pregelatinized starch samples (courtesy of Zentiva company) Characterization SEM, XRD, DSC, PM functional characteristics Preparation of API/starch mixtures 1 : 4

SEM images of maize starch Pregelatinized Native

Maize starch functional properties Starch ID A B C D E V/V 0 4.9 4.4 5.7 8.1 7.7 w H2O, % 8 8 8 7 7 w dis,20 C, % 10.3 6.4 10.9 8.9 6.8 w dis,35 C, % 12.2 13.4 13.5 10.6 8.0 E D C B A E D C B A 0 5 10 0 5 10 15 V/V 0 w dis,35 C, %

Apparent intrinsic dissolution Fill mixture to dissolution die Compress a compact in die and place in IDR IDR amount released Apparent IDR time

Dissolution results 0,2 API1 0,2 API2 c, g.l -1 c, g.l -1 2 2 2 2 0,1 0,1 2 2 1 2 1 3 2 1 3 2 1 3 1 3 1 3 1 3 1 3 2 2 1 2 1 3 1 3 3 2 1 3 2 1 3 3 0,0 0 30 t, min 60 0,0 12 1 12 11 2 22 3 3 333 13 0 30 t, min 60 Cumulative dissolution profiles of caffeine released from caffeine-starch matrix comprising different pregelatinized maize starch samples (A, B, C, D, E) measured in standard IDR apparatus (900 ml 0,1M HCl, 50 rpm)

Mathematical model Noyes-Whitney Sink conditions + resistance due to swollen layer dc dt * API wacapi 1 D API, ef Swollen layer thickness d dt 1 c * CAF CAF V D HL CAF HL r API 1 D * KA c API capi D CAF, ef c * ST ST D ST HL caffeine leaching starch matrix decay

Regression results - caffeine 0,2 API1 c, g.l -1 0,1 Starch ID A B C D E D API, cm 2.s 1 4.20 10 6 D ef /D API 180 181 135 30 25 R ST,dis, cm.s - 1 ( 10 3 ) 0.09 0.61 < 0.01 1.38 1.34 0,0 0 30 t, min 60

Correlation analysis API1 API2 200 D ef /D CAFF 100 0 0 3 5 V/V 0 7 9 7 11 w dis,(35 C), % 15 200 D ef /D CAFF 100 2 R ST, dis cm 2.s -1 0 4,0 5,0 V/V 0 6,0 0 11,0 w dis,(35 C), % 15,0 1 1 R ST, dis cm 2.s -1 starch, used in drug formulations, can significantly alter the active ingredient release profile different maize starches within the pharmacopeial requirements can exhibit substantial differences in their effect on drug dissolution retardation effect of starch on the release rate is determined by the effective diffusivity of active ingredient within the swollen starch layer by the rate of starch layer decay effective diffusivity strong function of swelling capacity starch matrix decay not simple function of starch solubility can depend on API/mixture properties

Dissolution Tools for API Characterization. Introduction on Dissolution API Characterization Intrinsic Dissolution Rate Apparent Dissolution Case Studies 1: VSCHT Doc. Zámostný-Effect of maize starch properties on drug dissolution rate Case Studies 2: VSCHT Doc. Zámostný - Dissolution Rate of Agglomerates, QbD Approach To formulation Conclusion 40

Dissolution Rate of Agglomerates - QbD Approach To formulation Case study 2

Aim of the work The overall rate of the API release depends on arrangement and interactions of APIs and excipients in dosage forms Affected by dosage form processing history Evaluate the API release rate from granules prepared by different granulation methods and understand the effects

Setup Powdered API API/excipients granulated by wet-granulation Compacted API/excipients Fractions of particle size 75 125 μm and 425 1000 μm Dissolution test: USP 4: 0.1N HCl, 37 C, open-loop arrangement Dissolution cell for powders and granulate

Release rate from different agglomerates powdered API (black) wet granulate (green) dry granulate (red) 425 1000 μm (filled markers) 75-125 μm (empty markers)

Release rate from different agglomerates dm dt Noyes-Whitney dm dt D D HL HL AC S A C s d p0 d 2D ef p k Ads Resistance to diffusion - binder K 1 Ads K Ads m m 1 m m Adsorption - MCC Wetting The data analysis allows us to determine the cause of possible dissolution problems at the design stage

Dissolution Tools for API Characterization. Introduction on Dissolution API Characterization Intrinsic Dissolution Rate Apparent Dissolution Case Studies 1: VSCHT Doc. Zámostný - Effect of maize starch properties on drug dissolution rate Case Studies 2: VSCHT Doc. Zámostný - Dissolution Rate of Agglomerates, QbD Approach To formulation Conclusion 46

Take-home Message. API biopharmaceutical characterization may be considered as time consuming but In-vitro testing is not expensive compared to in-vivo studies. It can guide and facilitate formulation development. These are good tools to de-risk biostudies. Different approaches can be used: XRPD, DSC, particle morphology Intrinsic / apparent dissolution Evaluation of different dissolution methods than USP 1 & 2 Use of different phs / media Finally, development time can be shortened. 47

Thank you for cooperation. Petr Zámostný, VSCHT Samir Haddouchi, SPS Pharma www.vscht.cz www.sotax.com www.sps-pharma.com