Deconvoluting Amorphous Solid Dispersion Dissolution

Transcription

1 Deconvoluting Amorphous Solid Dispersion Dissolution Jonathan Booth Formulation Science Section AstraZeneca Macclesfield PhysChem Forum 11 Meeting Nottingham, September 21 st 2011

2 Whats the Problem? ~ 1300 marketed drugs ~ 40 % poorly soluble (logs < -4) Frequency logs (predicted using ALOGPS software)

3 Solid Dispersions Intimate mixture of drug and water soluble/swellable excipient(s) - usually amorphous polymers. Surfactants/plastisers may be added Amorphous solid dispersions/solutions provide most potential for bioavailability enhancement due to solubility advantage of amorphous state Commonly used polymers are PVP-based, Celluloses and Methacrylates Key risks and challenges: Amorphous SDs are normally thermodynamically unstable at practical drug loads recrystallisation of amorphous drug generally reduces bioavailability Analytical testing Detecting low levels of crystallinity, etc Poor biopharm. understanding Sub-optimal dissolution methods and models

4 Dissolution Testing A tool for performance verification and understanding Bioavailability of oral dosage forms is dependant on release and solubilisation of drug, as only drug in solution can be absorbed For drugs with poor solubility dissolution is likely to be a rate limiting step in drug absorption Dissolution can therefore serve an indicator of product performance disintegration precipitation permeability k dd k precip k id solubilised drug k p absorbed drug dispersed drug particles dissolution

5 Solid Dispersion Dissolution Wetting Addition of hydrophilic carriers increases wettability of hydrophobic drugs leading to an improvement in dissolution performance Example: Ketoconazole/PVP θ Karavas, E et al; Eur.J.Pharm.Biopharm. 2006, 63,

6 Solid Dispersion Dissolution Carrier vs Drug Control Drug CARRIER-CONTROLLED DRUG-CONTROLLED Craig, D.Q.M. Int.J.Pharm. 2002, 231,

7 Solid Dispersion Dissolution Carrier vs Drug Control For carrier-controlled systems the dissolution profiles of the drug and carrier are identical Example: Mixtures of a poorly soluble drug and water soluble polymer Extruded amorphous solid solution Physical mix polymer drug polymer drug CARRIER-CONTROLLED DISSOLUTION DRUG-CONTROLLED DISSOLUTION

8 Solid Dispersion Dissolution Solubility Advantage of the Amorphous State amorphous ΔG ΔH T m S amorphous crystalline S crystal

9 Solid Dispersion Dissolution Particle Formation Solid dispersions typically yield (nano/micro) particles on dissolution Particles can be pre-formed or precipitate during dissolution under super-saturated conditions formed within/adjacent to the dissolving matrix or in bulk solution Particles may grow due to aggregation, ripening and crystal growth,or dissolve if the solution is under-saturated with respect to the solubility of the solid Example: Felodipine/PVP (90/10 w/w) : Dissolution in ph 6.5 / 2% Tween20 (37 o C) Karavas, E et al. Eur. J. Pharm. Biopharm. 2007, 66,

10 Solid Dispersion Dissolution Nucleation & Crystal Growth dr/dt = Growth rate S 0 = Crystalline solubility D = Monomer diffusion coefficient V m = Molar volume λ = DV m /K i with K i = Surface integration constant dr dt = - DVm ( S R + λ 0 C b ) J = k 1 e k [ ln(c /S )] 2 b 2 0 J = Nucleation rate (# supercritical nucleii / volume) k 1, k 2, = constants C b = Monomer bulk concentration S 0 = Crystalline solubility

11 Solid Dispersion Dissolution Solution Metastability The amorphous state of the drug provides the spring. Suitable inhibitor(s) in the formulation act as a parachute to maintain super-saturation. Brouwers, J et al; J. Pharm. Sci. 2009, 98 (8),

12 Solid Dispersion Dissolution Solution Metastability Example: impact of various excipients on the precipitation of a poorly soluble drug Spike 2 Spike 3 Excipient 5 Spike 1 Excipient 4 Excipient 3 Excipient 2 Excipient 1 Ability of excipients to maintain drug super-saturation : Excipient 5 ~4 > 3 > 2~1

13 Solid Dispersion Dissolution Solubilisation & Complexation In solution solid dispersion carriers can solubilise / complex the drug substance this can have an impact of dissolution performance. Interaction between drug and carrier can be assessed via the binding constant (K) Example: Ketoconazole/PVP Slope K 1:1 = S 0 Slope (1 Slope) S 0 = Crystalline solubility Balata, G et al; Asian Journal of Pharmaceutical Sciences 2010, 5(1), 1-12

14 Case Study Materials & Methods N O O O O Cl Cl Felodipine Poorly soluble: BCS II compounds S 0 ~ 1ug/ml Spray drier Small-scale fibre optic dissolution H C CH2 H C CH2 N O O O m CH 3 n Copovidone (VA64) Water soluble polymer Mw ~ 30kDa Press MRI/ UV flow cell

15 Case Study Characterisation of Solid Dispersions Spray dried solid dispersions of Felodipine and Copovidone are amorphous Intensity (Counts) 2 theta (degrees)

16 Case Study Dissolution of Pure Amorphous Felodipine Dissolution of amorphous Felodipine only reaches theoretical amorphous solubility in the presence of a crystallisation inhibitor (Copovidone in this case) acting as a parachute S amorphous predicted Felodipine Concentration (ug/ml) Crystalline Felodipine - Mean Amorphous Felodipine - Mean Amorphous Felodipine + 2% Copovidone in media - Mean Time/ sec ph o C [Felodipine] total = 100ug/ml

17 Case Study Dissolution of Spray Dried Powder Dissolution is very rapid especially at high polymer/drug - (transient) concentrations significantly greater than amorphous solubility can be achieved Need greater than 50% w/w polymer (dry state )to achieve solution metastability for this system corresponding to ratio of solution concentrations [polymer]/[drug] of at the maxima (plateau) of the dissolution profiles for the 70, 85 and 95% w/w polymer formulations 5% Felodipine 15% Felodipine Metastable zone height (ug/ml) Polymer Content (% w/w) 30% Felodipine Predicted amorphous solubility 50% Felodipine ph o C [Felodipine] total = 100ug/ml

18 Case Study Dissolution of Compacts Dissolution of the compacts is relatively slow (compared to the corresponding powders) Only reach theoretical amorphous solubility for the 5% Felodipine/95% Copovidone formulation 50% Felodipine formulation dissolution performance is comparable with a physical mix of crystalline drug and polymer 5% Felodipine 15% Felodipine 50% Felodipine ph o C [Felodipine] total = ug/ml

19 Case Study Powder vs Compact Dissolution Maximum Felodipine solution concentration is significantly lower for the compacts compared to the corresponding powders pointing to a difference in dissolution mechanism Attribute high extent (and rapid) dissolution of Felodipine from powdered solid dispersion to rapid water uptake and dispersal of highly porous/ high surface area matrix driven by conditions of relatively high convection Attribute low extent (and slow) dissolution to lower porosity/surface area, slower water uptake and precipitation/crystallisation of Felodipine at/near the dissolving interface driven by conditions of relatively low convection Highlights the importance of compaction (and convection) on dissolution performance Maximum Felodipine Concentration (ug/ml) Powder Compact Felodipine Loading (% w/w)

20 Case Study MRI Studies of Compact Dissolution 5% (and 15%) Felodipine formulation steadily erodes erodes and dissolution proceeds to completion 50% Felodipine formulation swells and remains intact Fel-Copov MRI Sequences

21 Case Study MRI Studies of Compact Dissolution 5% Felodipine / 15% Felodipine 50% Felodipine long long short short 5 and 15% Felodipine formulations erode at the same rate (carrier-control) whereas the 50% formulation swells (drug-control)

22 Case Study Impact of Nucleation and Crystal Growth 5% Felodipine/ 95% Copovidone Solution Concentration (ug/ml) Measured solution concentration Theoretical released due to erosion Precipitated Drug Time (h)

23 Case Study Proposed Dissolution Model for Compacts D = k ([Fel] S am Fel ) d am init, x am d cryst init, 1-x am G = G 0 ([Fel]/S cryst Fel 1)

24 Case Study Proposed Dissolution Model for Compacts Good fits of data from 5 and 15% formulations to model without need to include nucleation 5% Felodipine/ 95% Copovidone R 2 = 0.99 d am init, x am d cryst init, 1-x am 15% Felodipine/ 85% Copovidone R 2 = mm/min (MRI) 5% Felodipine 15% Felodipine x am d init am 165nm 600nm d tinit crys 165nm 600nm

25 Case Study Summary & Conclusions Dissolution behaviour of Felodipine from amorphous solid dispersions with Copovidone shows a strong dependence on drug/polymer ratio Dissolution of spray dried solid dispersion powders is rapid and concentrations significantly in excess of the predicted/measured amorphous solubility were observed especially in formulations with high polymer levels Dissolution of Felodipine from compacted spray dried solid dispersions is much slower than from the corresponding uncompacted powders and for the 5 and 15% Felodipine formulations proceeds by linear erosion with identical rates suggesting carrier control. At higher drug loadings the system becomes dominated by the drug and the system swells rather than erodes. Even at 5% drug load the effects of precipitation are significant A dissolution model based on measured and fitted parameters was developed to accurately describe the observed dissolution profiles key feature is the formation/release of amorphous and crystalline particles to act as a generator and sink for dissolved Felodipine

26 Future Work Further validation/development of the dissolution model Move towards more biorelevant media and hydrodynamics Test further drug/carrier systems to study the impact of material properties on dissolution mechanism Study the impact of different processing methods on dissolution mechanism and performance of solid dispersions

27 Acknowledgements Felodipine Case Study Zoe Langham Les Hughes Gavin Reynolds Stephen Wren Other Data/Slides Stephen Bush Lennart Lindfors Kasia Nurzynska Ben Read Kevin Treacher