Solubility enhancement of poorly soluble API using cellulose derivatives. 28th April 2014 Shilpa Mistry

Transcription

1 Solubility enhancement of poorly soluble API using cellulose derivatives 28th April 2014 Shilpa Mistry

2 Class up to improve drug solubility BCS :Biopharmaceutics Classification system *1 More than 60% of candidate drug Absorption (Permiability) 90% (10-6) Class Ⅱa/ IIb Class Ⅳ Class Ⅰ Need to Improve 0.1mg/m Solubility Class Ⅲ Formulation Change (hard technique) Chemical Change (relatively easy)

3 Solid dispersion Physical mixture Solid dispersion Drug (Crystal) Drug (Molecule) Carrier (Polymer) Amount dissolved (mg/ ml) Solid Dispersion Drug (Crystal) solubility Physical mixture Time (min) Drug crystal amorphous (molecule) Solubility Low High Stability Stable Unstable (recrystallization) 3 Drug & polymer miscibility Stable in the process

4 Approach to Improve drug solubility Physical modifications -Micronization -Complexation (Surfactants, CyD, etc.) -Polymorphs -Solid dispersion (amorphous) Chemical modification -Soluble prodrugs -Salts Requirements of a good solid dispersion: Superstation release profile (3hrs), high API content, Good stability. 4

5 Solid dispersion Approach to Improve Drug Solubility First paper Sekiguch and Obi, Chem. Pharm. Bull Eutectic mixture (Sulfathiazole-Ascorbic acid, acetoamide, nicotineamide, urea ) Chiou and Riegelman, J. Pharm. Sci Solid dispersion (Griseofulvin-PEG6000) First commercial product -Sepamit Nifedipine Solid Solution by Kanebo since 1981 Few products on the market : because of stability issues manufacturing issues other opportunities for delivery of insoluble compounds 5

6 Preparation of solid dispersions Drug Polymer Solvent Spray Dry Spray dryer Spray Coating Co-precipitation Fluidized bed Core: lactose etc. Powder Capsule or Tablet Hot melt extrusion Using poor solvent Drug Polymer Powder Injection moulded tablets

7 Preparation of Solid dispersion Solvent method Spray drug-polymer solution Co-soluble process Miscible to solvent Hot Melt Extrusion Heat and shear drug-polymer mixture Co-melt process Thermal misible 7

8 Particle morphology Solid dispersion x1000 x250 x250 Spray Drying x1000 x Spray Drying (lactose) Melt Extrusion (milled)

9 Carrier substances for solid dispersion Polyvinylpyrrolidone Polyethylene glycols Cellulose derivatives -HPMC, HPC, HPMCP, HPMCAS Polyacrylates Urea Sugar 9

10 Structure Enteric coating agent (cellulose derivatives) HPMC HPMCAS : Methyl Hydroxypropyl : Acetyl hydrophobic : Succinoyl hydrophilic (anionic dissociation)

11 HPMCAS : Shin-Etsu AQOAT H OR CH 2 OR O OR H H H O H H O OR H H O H CH 2 OR H OR CAS; , listed in JPE, USP/NF R= -H, -CH 3, -COCH 3, -COCH 2 CH 2 COOH -CH 2 CH(OH)CH 3, -CH 2 CH(CH 3 )OCOCH 3, -CH 2 CH(CH 3 )OCOCH 2 CH 2 COOH Enteric coating agent Sustained release coating Multi functional substituent hydrophobic H-bonding Amorphous polymer chain network

12 Grades of HPMCAS ph dependent solubility Vitamin B 2 tablet 100 Acetyl Succinoyl (%) (%) 80 AS-LG/LF 8 15 AS-MG/MF 9 11 AS-HG/HF 12 7 G: Granular grade (HME and SDD) F: Fine grade (Aqueous & dry coating) % dissolved at 30 min AS-LF LG AS-MF MG AS-HF HG ph

13 Glass transition temperatures HPMC AQOAT (HPMCAS) HPMCP : Succinoyl : MeO or HPO : Acetyl : Phthalyl Tg: 165 C (P-606) Tg:120 C (AS-L) 130 C (AS-M) 135 C (AS-H) Tg: 145 C (HP-55)

14 Screening study Preparation API and polymer were dissolved in a mixed solvent (Ethanol:Dichloromethane = 1:1w/w) and then sprayed onto Teflon sheet and grounded. Polymers Hypromellose acetate succinate (HPMCAS: Shin-Etsu AQOAT AS-MF, Shin-Etsu Chem.) Hypromellose phthalate (HPMCP: HP-55, Shin-Etsu Chem.) Hypromellose (HPMC: Pharmacoat 606, Shin-Etsu Chem.) Polyvinylpyrrolidone (PVP: Kollidon K30, Sigma)

15 Screening study (solvent method) Nifedipine Griseofulvin Dipyridamole Carbamazepine Mw: 346 Mw: 352 Mw: 504 Mw: 236 water solubility: mg/mL water solubility: mg/mL water solubility: 0.004mg/mL water solubility: 0.224mg/mL solubility at ph6.8: mg/mL solubility at ph6.8: mg/mL solubility at ph6.8: mg/mL solubility at ph6.8: 0.163mg/mL solubility at ph1.2: solubility at ph1.2: solubility at ph1.2: solubility at ph1.2: mg/mL mg/mL >2.5mg/mL 0.192mg/mL NP GRF DIP CBZ

16 Screening study (solvent method) Dissolution test (ph6.8) Dissolved NP (μg/ml_) Dissolved DIP(mg/L) NP crystal HPMCAS HPMC HPMCP PVP Time (min) DIP crystal HPMCAS HPMC HPMCP PVP Time (min) HPMCAS solid dispersion improved drug dissolution Dissolved GRF (mg/l) Dissolved CMZ (mg/l) HPMCAS HPMC HPMCP PVP GRF crystal Time (min) Time (min) CBZ crystal HPMCAS HPMC HPMCP PVP

17 Screening study (solvent method) Inhibition effect of recrystallization of dissolved NP 100 (ph6.8), NP:carrier 1:1 Dissolved NP (μg/ml_100μg/ml) HPMCAS HPMCP HPMC PVP NP Crystalline Time (min)

18 Screening study (solvent method) Stability (Storage condition: 50 C in the closed bottle) Assay by HPLC (%) Dissolution of NP at 10min. (ph6.8) (mg/l_50mg/l) initial 18 months initial 18 months NP HPMCAS HPMC HPMCP PVP

19 Screening study (solvent method) Hygroscopicity Equilibrium moisture content (%) PVP HPMC HPMCP HPMCAS Relative humidity (%)

20 Large scale spray drying Formulation: HPMCAS-LG: Felodipine 3:1 Solvent, Acetone Preparation solution: Felodipine was dissolved in acetone and the HPMCAS was added slowly and mixed for one hour. Equipment: GEA Niro 12.5CC pilot plant Equipped with 4 pneumatic hammers, HEPA filters & Cyclone to collect the primary powder fraction. Including the controlled room

21 Process parameters Test Number Trial Temp(0C) Nozzle Solid content Pressure Feed Rate Particle Size LOD Quantity Bulk density (g/ml) Inlet Outlet (mm) (%) (bar) (kg/hr) D50 (um) (%) (kg) Lose Tap

22 Post Drying Before After Test Number Particle Size LOD Quantity Mesh size Temperature Air flow Time LOD after D50 (um) (%) (kg) (µm) ( C) (min) (%)

23 X-ray diffraction No.1 No.2 No.4 No.6 No.10 Intensity (cps) felodipine crystal θ ( )

24 14µm 26µm 49-53µm µm

25 Summary Particle size has a large effect on your release profile and need to take are that when scaling up to production. With the larger particle size the flow improves therefore can avoid granulation step. Post drying is essential to remove the residual solvents. Increasing our solid content to 12.4% gave the best results which results to shorter processing times and good yield.

26 Screening study (solvent method) XRD solid dispersion (API: carrier = 1:2) NP GRF* (GRF:carrier 1:4) Intensity (csp) PVP HPMCP HPMC HPMCAS Crystalline HPMCAS PVP HPMCP HPMC HPMCAS Crystalline DIP Intensity (cps) θ ( ) PVP HPMCP HPMC HPMCAS Crystallin CBZ Intensity (cps) θ ( ) PVP HPMCP HPMC HPMC Crystalline θ ( ) Amorphous solid dispersion θ ( ) 30 40

27 Operation window for melt extrusion HPMCAS shows the wider operation window among cellulose derivatives Tg N.D Tg/Tdecomp. ( C) Tdecomp Tg Pulp HPMC HPMCAS HPMCP PVPVA

28 Thermodynamic properties of HPMCAS DSC and TGA measurement DSC (mcal/s) Pulp HPMC HPMCAS Temp(ºC) Weight Loss (%) Glass Transition temperatures were appeared in cellulose derivatives (HPMC & HPMCAS) Thermal plasticity (HPMC & HPMCAS) Similar thermal decomposition temperature Pulp HPMC HPMCAS Temp (ºC)

29 HME- Feasibility studies Labo Scale Apparatus: MiniLab (Haarke Thermo) Sample: 5g (Drug-polymer[1:2] mixture) Condition: 170 C, 20rpm[screw] Milled after extrusion Formulation: NP/AQOAT (AS-L,M,H) 1/2 NP/KollidoneVA64 * 1/2 & 1/6 *: Kollidone VA64 (BASF; PVPVA copolymer) Evaluation Drug crystallinity Improvement of drug dissolution 29

30 Improvement of Drug Dissolution 100 Dissolved NP (mg/l_100mg/l) NP/AS-LF 1/2 NP/AS-MF 1/2 NP/AS-HF 1/2 NP/Kollidone VA64 1/2 NP/Kollidone VA64 1/6 NP/KollidoneVA64 1/2(160 ) Drug crystal (intact) NP Dissolution in ph Time (min) Improvement (sustained high drug release): HPMCAS > Kollidone VA64

31 Design of experiments- optimum process parameters Formulation: Shin-Etsu Aqoat HPMCAS-MG: Ibuprofen 2:1 Pharma 11 Thermo Scientific, Germany) Temperatures (Degrees) Torque (%) Speed(rpm) Feeder(kg/hr) Pressure(bar) Melt Temperature ( Degrees) Initial Zone 2 Zone 3 Zone 4 Zone 5 Zone 6 Zone 7 Zone 8 Die

32 Extrudates During processing the measured extruder torque was 25%. Our general recommendation is to use extrusion temperature for HPMCAS is 150ºC but in the presence of 33% ibuprofen it could be readily processed at 100ºC. Extruded pellets This suggests that ibuprofen acted as a plasticiser and allowed processing at a reduced temperature.

33 Injection moulding & Results Mini Jet (Thermo Scientific, UK)120 C of the injection piston and 30 C of the mould Pressure: 400 bar over 5 seconds and post pressure: 300 bar 2 sec

34 Hotmelt Extrusion (Pure HPMCAS, Haake MiniLab) grade lot viscosity Loss on Substituent (%) free acid (%) Total AS-MF cp Drying MeO HPO Ac Suc Succinic acid Acetic acid acid (%) Temp. ( ) roter (rpm) before HME Cleavage of Succinic Groups

35 Stability for Melt Extrusion Discussion: -Cleavage of Succinoyl Groups Free acid increase (dissolution ph shifts to higher) -Color Change (more yellowish) -Slight Reduction in Molecular weight at 200 C Possibility of interaction between API and free acid

36 Storage stability (NP solid dispersion) NP content of solid dispersion Assay by HPLC Storage period (18M) (%) Initial 40 C, 75%RH 50 C, closed bottle NP AQOAT HPMC HPMCP PVP Eudragit L In most cases, drug content remain the same level. (Stable) 36

37 Storage stability (NP solid dispersion) Equilibrium moisture content (25 C) Equilibrium moisture content (%) PVP HPMC HPMCP HPMCAS Relative humidity (%) AQOAT is lower hygroscopic. PVP is highly hygroscopic. absorb moisture recrystallize

38 AQOAT-NP solid dispersion pellet 100 Dissolution amount of NP (μg/ml) CH2Cl2 Ethanol Methanol Aceton Core beads : Nonpareil -101 Spray solution : 9% AS-M/NP (2:1) solution* *Solvent : CH2Cl2/EtOH, MeOH, Acetone Layering amount : 10% NP rotary fluidized bed granulator core 0 NP only Time (min) Solid dispersion layer 38

39 Conclusion AQOAT could be useful as carrier of solid dispersion. Benefit: Amorphous SD with small carrier ratio Great improvement of drug dissolution (enteric) Inhibition of recrystallization Good stability

40 HME Cleaner The cleaner consist of Hypromellose and water soluble plasticizer which is commonly used in pharmaceutical applications. How to use the cleaner: Samples are available in 4kg bags

41 Examples of HME Cleaner The cleaner consist of Hypromellose and water soluble plasticizer which is commonly used in pharmaceutical applications.

42 Microprecipitated Bulk Powder (MBP) Method m.p ºC Solubility Aqueous < 0.1 mg/ml Organic Solvents (mg/ml) DMSO > 50 Vemurafenib (For Melanoma) MeOH 4.57 AcCN 1.40 CH 2 Cl Acetone < 6 42 Shah et al. J. Pharm. Sci. 102 (3), 2013

43 Coprecipitation Process for Preparation of MBP HPMCAS, HPMCP, Eudragit L Vemurafenib Ionic polymer Crystalline API Drug + polymer dissolve in solvent Cold dilute acid / base Solvent removal Aqueous wash Drying 43 Shah et al. J. Pharm. Sci. 102 (3), 2013

44 Dissolution Profiles of Vemurafenib MBP with HPMCAS MBP with Eudragit L USP Apparatus 2 (b) with 0.09% HTAB 44 Shah et al. J. Pharm. Sci. 102 (3), 2013

45 Quality by Design (HPMCAS) Factors that may affect to performance Substitution level: Viscosity: Impurities: Acetyl / Succinoyl Methoxy / Hydroxypropoxy (Molecular weight) Free acetic acid Free succinic acid Residual salt (sodium acetate) Moisture 45

46 Factors that may affect to performance Acetyl / Succinoyl Methoxy / Hydroxypropoxy - Affect to API dissolution. - May affect to stability of API - Subject to hydrolysis - Recommended to set up a range - May affect to API dissolution Viscosity (Molecular weight) - May affect to API dissolution 46

47 Effect of Succinoyl / Acetyl Groups AS-LG AS-MG AS-HG Dissolved NP (mg/l) Sample C Sample B Sample A Dissolved NP (mg/l_100mg/l) Sample F Sample E Sample D Dissolved NP (mg/l_100mg/l) Sample G Sample H Sample I Time (min) Time (min) Time (min) *The original solubility of Nifedipine is 12 mg/l AS-LG AS-MG AS-HG Sample ID A B C D E F G H I Succinoyl, % Acetyl, %

48 Impurities within HPMCAS -Acetic acid / Succinic acid -Sodium acetate -Moisture - May affect stability of API. - Gradually increases during storage. (Except sodium acetate) Shin-Etsu is open to communicate customers to discuss QbD strategy such as Extreme samples, Variability Data, and Custom Specifications. 48

49 Recent approval of solid dispersion using Shin-Etsu AQOAT (HPMCAS) Approved on Mft Brand API Disease May, 2011 Vertex INCIVEK Telaprevir Hepatitis C Aug, 2011 Roche ZELBORAF Vemuratenib Melanoma Jan, 2012 Vertex KALYDECO Ivacaftor Systic Fibrosis Nov, 2013 Merck NOXAFIL TAB Posaconazole Immune deficiency