MELT EXTRUSION AND MELT GRANULATION PROCESSES IN DEVELOPMENT OF DRUG PRODUCTS

Transcription

1 MELT EXTRUSION AND MELT GRANULATION PROCESSES IN DEVELOPMENT OF DRUG PRODUCTS Abu T. M. Serajuddin, Ph.D. St. John s University, Queens, New York serajuda@stjohns.edu; Phone:

2 Hot Melt Extrusion Technology General Understanding : Hot melt extrusion is a singlestep process suitable to manufacture high-energy solids (e.g., solid dispersion) Homogeneous mixture of active, polymer plasticizer, surfactant 2

3 Extrusion Detail Melting & Mixing Ref: Adapted from Scott Martin (ThermoFisher Scientific ) presentation

4 Basic Screw Elements Conveying Elements Feeding Sections Blending Melt Exchange (longitudinal mixing) Pumping, Pressurization Degassing / Venting Mixing Elements Blending Intense Shear Introduction Dispersive Mixing Distributive Mixing Ref: Adapted from Scott Martin (ThermoFisher Scientific ) presentation

5 Extrusion System Length-to-Diameter Ratio 25:1 l/d 40:1 l/d Ref: Adapted from Scott Martin (ThermoFisher Scientific ) presentation

6 Application of Melt extrusion High-energy Solid and Solid Dispersion 6

7 Heat content (enthalpy, H) Formation of High-energy Solid liquid High-energy state Heat of fusion Crystal Low energy state T g (drug) 7 Temperature T melting

8 Heat content (enthalpy, H) Conversion to Solid Dispersion Storage temperature Drug only Drug - polymer miscible blend (solid dispersion) Elevated T g 8 T g (drug) Temperature T g (mixture)

9 What is Solid Dispersion? the dispersion of one or more active ingredients in an inert carrier or matrix, where the active ingredients could exist in finely crystalline, solubilized or amorphous state - Chiou and Riegelman, J Pharm Sci 1971, 60, Drug (crystalline) + Carrier (amorphous) No miscibility Partial miscibility Complete miscibility

10 Solid Dispersion Application of Melt Extrusion 10

11 Solid Dispersion by Hot Melt Extrusion Homogeneous mixture of active, polymer plasticizer, surfactant 11

12 Advantages of Melt Extrusion Continuous Process Complete conversion to amorphous state, reproducible and no local melting (unlike co-milling or co-melting) Solid dispersion without solvents Avoids solvent toxicity Reduced cost/environment impact No drying issues/residual solvents Sustained-release capabilities High potency capabilities (closed system)

13 Challenges with Melt Extrusion Feed port Heated barrel with temperature zones Motor Conveying zone Mixing zone Die Temperature must be higher than the melting temperature (at least 20 C higher) for complete conversion to amorphous form and ease of processing (reduce viscosity) Risk associated with chemical stability thermo-labile compounds High Tg of commonly used polymers ( C) need suitable plasticizers; temperature must be > Tg Lack of miscibility between drug and polymer 13

14 Why So Few Solid Dispersion Products? Most Significant Impediments Lack of appropriate carriers/polymers Immiscibility with drugs leads to phase separation Incomplete drug release Difficulty in predicting physical stability Solid dispersions are usually amorphous Crystallization of drug, carrier or both leads to physical instability

15 Some Common Polymers Polymer Trade Name Tg Poly(ethylene oxide) Polyox WSR -67 Polyethylene glycol Carbowax -20 Poly (vinyl pyrrolidone) Kollidon 168 Poly (lactide-co-glycolide) PLGA Polyvinyl alcohol Elvanol 85 Ethyl cellulose Ethocel 133 Hydroxypropyl cellulose Klucel 130 Hydroxypropylmethyl cellulose Methocel 175 Aminomethacrylate colpolymer Eudragit RS/RL Poly(dimethlyaminoethylmethacryl ate-co-methacrylic ester) Poly methcyrlic acid-comethylmethacrylate) Eudragit E 50 Eudragit S 160

16 Carrier Screening Solid Miscibility Drug-carrier miscibility may lead to singlephase solid dispersion systems Drug-carrier solid miscibility is the first step in identifying a suitable carrier for a drug candidate

17 Rev Heat Flow (W/g) Rev Heat Flow (W/g) What is Drug-Carrier Miscibility? Tg of drug Tg of solid dispersion Tg of solid dispersion Tg of polymer Exo Up Temperature Exo Up Temperature Partial miscibility Full miscibility

18 Carrier Screening Solid Miscibility versus Solid Solubility Solid miscibility, however, does not guarantee physical stability Solid solubility is a better predictor of physical stability Ref: Vasanthavada et al., Phase Behavior of Amorphous Molecular Dispersions: Determination of the Degree and Mechanism of Solid Miscibility, Pharm. Res., 2004, 21:1598 & 2005, 22:440

19 Heat Flow (W/g) Effect of Storage Condition Drug-Carrier Miscibility Pure polymer T g eq T g of pure polymer T g of fresh SD Fresh SD T g of drug stability conditions T g of drug + polymer Temperature dissolved drug plasticizes the polymer Ref: Vasanthavada et al., Phase Behavior of Amorphous Molecular Dispersions: Determination of the Degree and Mechanism of Solid Miscibility, Pharm. Res., 2004, 21:1598 & 2005, 22:440

20 Solid Dispersion by Melt Extrusion Case Study 20

21 Lower Temperature Melt Extrusion A Case Study Compound A 15% degradation during melt extrusion of crystalline form with PVP or HPMC Molecular weight Melting point 180 C Glass transition [T g ] ~120 C Chemical form Weak base pk a 10.03; 2.91 Solubility in water (RT) ph 1: 0.03 mg/ml ph 3-9: <0.003 mg/ml 21

22 Lower Temperature Melt Extrusion A Novel Strategy Amorph. extrudate Crystalline drug subs. + Polymer High temperature melt extrusion Drug degradation Amorphous drug subs. + Polymer Lower temperature melt extrusion Stable product Ref: Lakshman & Serajuddin et al., Molecular Pharmaceutics, 5: ,

23 Amorphous Form* of Compound A Used for Melt Extrusion Nature of amorphous form as a function of temperature 25 C 120 C 126 C 140 C Miscibility of amorphous form with PVP K C 140 C 155 C 170 C *Amorphous form prepared separately by solvent evaporation

24 DSC Analysis of Melt Extrudates Melt extruded with PVP K-30 at 20 and 40% w/v drug load using sorbitol as plasticizer (30% and lower drug load). No significant drug degradation. 40% w/w drug 30% w/w drug 20% w/w drug 15% w/w drug 24

25 Relative Bioavailability of Melt Extruded Solid Dispersion (Compound A) Plasma conc. (ng/ml) Mean PK profiles of Compound A in dogs at a constant drug load % drug TKA A & Poloxamer triturate, capsule capsule 20% melt Melt extrusion, K90, capsule 20% melt extrusion, K90 & surfactant,capsule w/sls, capsule 20% spray drying, tablet tablet 20% spray granulation, tablet tablet old 20% 20% melt melt extrusion, extrusion K30, capsule 20% rotavap, tablet Time (hrs) 25 Pooled data from two PK dog studies

26 Recent Breakthrough in Granulation Technology - Use of Twin-screw Extruders

27 Melt Granulation Technology Traditional

28 Melt Granulation Melt granulation is a process by which pharmaceutical powders are efficiently agglomerated by the use of a binder which melts during the process

29 Melt Granulation Traditional Methods Traditional Methods High-shear melt granulation Fluidized bed melt granulation Tumbling melt granulation High-shear granulation Heat transfer is a major issue Relatively high temperature cannot be used

30 Melt Granulation Traditional Methods Granulating Agents Used (Melting Points: C) Poloxamers Polyethylene glycols Carnauba wax Beeswax Paraffin wax Stearic acid Hydrogenated castor oil

31 Use of Twin-Screw Extruders

32 Melt Granulation Using Twin-Screw Extruder Feed port Heated barrel with temperature zones Motor Conveying zone Mixing zone Die Relatively short dwell time in the heated barrel Temperature maintained below the melting temperature of drug substance but above the glass transition (or melting) temperature of polymer used Unlike older, traditional methods, temperature can be raised as high as 200⁰C, making the use of a wide range of polymeric materials possible A continuous process 32

33 Much Wider Range of Polymers May be Used Polymer Trade Name Tg Poly(ethylene oxide) Polyox WSR -67 Polyethylene glycol Carbowax -20 Poly (vinyl pyrrolidone) Kollidon 168 Poly (lactide-co-glycolide) PLGA Polyvinyl alcohol Elvanol 85 Ethyl cellulose Ethocel 133 Hydroxypropyl cellulose Klucel 130 Hydroxypropylmethyl cellulose Methocel 175 Aminomethacrylate colpolymer Eudragit RS/RL Poly(dimethlyaminoethylmethacryl ate-co-methacrylic ester) Poly methcyrlic acid-comethylmethacrylate) Eudragit E 50 Eudragit S 160

34 Development of High Dose Tablet- Case Study Ref: M. Vasanthavada, Y. Wang, J. P. Lakshman, W. Tong, Y. M. Joshi, A. T. M. Serajuddin. Application of Melt Granulation Technology Using Twin-screw Extruder in the Development of Modified-release Oral Formulation for a High-dose Drug Product. J. Pharm. Sci. 100, (2011)

35 Development of High-Dose Modified Release Tablet A Case Study Immediate release 400-mg marketed tablet weighs ~775 mg What will be the weight of a 800-mg tablet? 800 mg drug substance in its salt form weighs ~960 mg Is the development of a single-unit tablet formulation feasible?

36 Challenges in Development of High-Dose Tablets Active pharmaceutical ingredient (API) in a tablet is often <50% Major tabletting issues with higher drug load The formulation development becomes very difficult, if not impossible, if at least 25% of the weight of a tablet is not excipient It becomes even more challenging for a modified release tablet, where at least 30-40% of the weight must be a release-controlling polymer, in addition to other excipients The maximum acceptable tablet size is mg For mg API, tablet size becomes unacceptably high of mg

37 Compositions of High Dose Tablets (960 mg Salt Equivalent per Tablet) Formulation No. API* [%w/w] Polymer %w/w Tablet weight [mg] MR1 94 Hydroxypropyl cellulose (Klucel HF) MR2 89 Hydroxypropyl cellulose (Klucel HF) MR3 89 Ethyl cellulose 100cP MR4 89 Hydroxypropylmethyl cellulose K100M + Ethyl cellulose 100cP * Drug load in the final tablet, since all formulations contained 1% w/w magnesium stearate as lubricant to aid in tabletting. 37

38 Melt Granulation Process Used A 16 mm co-rotating twin screw melt extruder (Thermo Fischer Scientific Inc., Germany) with a length-to-diameter ratio of 40-to-1 was used. The extruder barrel was divided into 6 temperature zones: 50, 110, 130, 170 and 185 C, with the cooler zone positioned towards the feeder and the warmer one towards the exit. The maximum processing temperature of 185 C was below the melting temperature of 212 C for the API A volumetric feeder (Brabender Technologie, Germany) with a unique pulsating mechanism and single horizontal feed screw was used to feed the powder. The pre-mix was fed directly into the extruder at a constant volumetric rate equivalent to 20 g/min. 38

39 39 Processing Conditions

40 Drug Release from Tablets (960 mg mesylate salt, 800 mg free base equivalent per tablet) MR 1 HPC 5% MR2 HPC 10% MR 3 EC 10% MR 4 HPMC 5% + EC 5% 40

41 Confocal Raman Microscopic Study Hydroxypropyl Cellulose Polymer overlay 50µm 41 API 50µm HPC 50µm Mg Stearate 50µm

42 Tablet Surface MR 1 s08184 m04 50µm 42

43 Development of High Dose Tablet- Metformin HCl Case Study J. P. Lakshman, J. Kowalski, M. Vasanthavada, W. Q. Tong, Y. M. Joshi, A. T. M. Serajuddin. Application of melt granulation technology to enhance tabletting properties of poorly compactible drug substance at high dose. J. Pharm. Sci. 100, (2011).

44 Challenges in Development of Metformin HCl Tablet Metformin hydrochloride exhibits minimal moisture sorption; however, the small amount of moisture sorbed is enough to dissolve large amounts of the drug. 44 Moisture desorption leaves behind metformin hydrochloride particles with solid bridges. In worst cases, extensive formation of solid bridges could result in free flowing powder transforming overnight into a solid block. With wet granulation or solvent granulation, this ability of metformin leads to changing granulation flow, density, tablet hardness, disintegration/ drug release that is difficult to control. Further, poor tablet compaction and process robustness become key concerns because of the need for high drug load in the formulation.

45 Composition of Metformin HCl Tablet Ingredients Amount/tablet (mg) %w/w Metformin hydrochloride % Hydroxypropylcellulose % Purified water q.s. n/a (or ethanol: isopropanol 95:5) Second drug substance 25.0/ %* Magnesium stearate % Total core weight 1134/1159 *dry mix with granules

46 Granulation Processes for Metformin HCl Tablet Moist granulation was carried out using a high shear Collete-Gral granulator. About 2.2 to 2.5% w/w water was sprayed over 4 min and granution was continued for 4 more min at high plough speed. No drying was employed. Melt granulation was performed using a 16-mm ThermoPrism Melt Extruder. A maximum process temperature of C together with an extruder screw speed of rpm and feed rate of kg/hr was used. All tablet compressions were performed using a Manesty Betapress or Korsch press after lubrication with magnesium stearate. 46

47 Tablet Hardness [N]. Moist Granulation Effect of Moisture Content and Drying on Tablet Hardness 90 a b Measured (a)immediately following tablet compaction and (b)after tray-drying the tablets for 24 hours at 50⁰C Compaction Force [kn] Initial moisture levels: 1.45%; 1.54%; 1.60%; 1.67%; 1.77%; 1.80%; 2.08%; 2.12%; x 2.21%.

48 Friability, 500 drops [%] Moist Granulation Effect of Moisture Content and Drying on Tablet Friability 8% 6% 4% 2% 0% a Measured (a) immediate following tablet compaction and (b) after tray-drying the tablets for 24 hours at 50⁰C. 48 8% 6% 4% 2% 0% Compaction Force [kn] b Initial moisture levels: 1.45%; 1.54%; 1.60%; 1.67%; 1.77%; 1.80%; 2.08%; 2.12%; x 2.21%.

49 Tablet Hardness (N) Melt Granulation Effect of Processing Condition on Tablet Hardness Temperature, feed rate, screw speed and magnesium stearate level : : 180ºC, 40 g/min, 120 rpm and 0.75%; : 140ºC, 40g/min, 120 rpm and 0.75%; : 140ºC, 40 g/min 120 rpm and 1.25%; : 180ºC, 40 g/min, 120 rpm and 1.25%; : 160ºC, 30 g/min, 210 rpm and 1.00%; : 160ºC, 30 g/min, 210 rpm and 1.00%; +: 180ºC, 20 g/min, 300 rpm and 0.75%; Compaction Force (kn) x: 140ºC, 20 g/min, 300 rpm and 1.25%; : 140ºC, 20 g/min, 300 rpm and 0.75%.

50 Melt Extrusion Effect of Processing Condition on Tablet Friability % Friability (500 drops) C 40g/min 120rpm 0.75% C 20g/min 300rpm 1.25% 180 C 40g/min 120rpm 1.25% 140 C 40g/min 120rpm 1.25% 140 C 40g/min 120rpm 0.75% Hardness (N)

51 Melt Granulation: Application in Continuous Processing Cooling Powder Feeding Sizing/Sieving Powder Mixing Tabletting/Spray Sieving (optional) Lubrication Coating Melt Granulation 51 Packaging

52 Conclusions - Melt Extrusion Technology More drug in a tablet leads to smaller tablet size!! Same dose Creating a safer environment with no organic solvents Over 90% drug per tablet Melt Granulates [Drug Product] Conv. technology Melt granulation technology Drug + Ref: Andreas Gryczke, RÖHM GmbH & Co. KG, Darmstadt Specialty Acrylics / Pharma Polymers A Continuous Manufacturing Process Melt granulation A promising technology + Polymer Reducing cost with fewer manufacturing steps & IP protection