PHYSICAL STABILITY OF SPRAY DRIED SOLID DISPERSIONS OF AMORPHOUS TOLFENAMIC ACID AND POLYVINYLPYRROLIDONE K-30

Transcription

1 PHYSICAL STABILITY OF SPRAY DRIED SOLID DISPERSIONS OF AMORPHOUS TOLFENAMIC ACID AND POLYVINYLPYRROLIDONE K-30 Copenhagen, Denmark

2 Outline of Today s Presentation Introduction Spray drying method Amorphous versus crystalline material Stabilization - solid dispersions Specific study Tolfenamic acid Methods Results (stability, dissolution) Summery Side 2

3 Spray Drying Simple up-scaling. Unique ability to produce specific particle size and volatile content regardless of dryer capacity Continuous reliable operation. Powder quality remains constant throughout the dryer run time under constant operating conditions Ability to handle heat sensitive, thermoplastic and/or hygroscopic materials Side 3

4 Spray Drying - Continued Ability to handle solutions, suspensions, emulsions, pastes or melts Ability to handle materials under cgmp and aseptic drying conditions Ability to handle hazardous substances i.e. flammable solvents, dust explosion hazards, toxic materials Wide choice of spray dryer designs allows product specifications to be met by tailoring the design Side 4

5 Examples of Spray-Dryers Laboratory scale Pilot scale Production scale Side 5

6 Applications in the Pharmaceutical Industry Formation of micro-particles Inhalable products Particle size Particle size distribution Micro encapsulation Controlled Release formulations Masking of a bad taste Polymorphism Solubility/dissolution Side 6

7 Key Elements in Spray Drying Atomization of liquid feed into a spray of droplets Droplet-Gas Contact mixing and flow pattern Drying of Droplets moisture / volatiles evaporation (~ 10 sec.) Product Recovery separation of particles from the gas Side 7

8 Atomization Rotary atomizer Pressure nozzle Two-fluid nozzle fountain mode Two-fluid nozzle Co-current mode Side 8

9 Droplet-Gas Contact Ref.: Masters 2002 Side 9

10 Drying From Droplet to Particle Formation of surface Drying rate Constant rate period (Saturated surface) Heating up Falling rate period (liquid/vapour diffusion) time Dry particle Ref.: Masters 2002 Side 10

11 Schematic picture of spray drying process Feed flow T in Nozzle gas flow 2 fluid nozzle Nozzle gas flow rate Feed flow rate Heater Drying chamber Cyclone Bag filter Exhaust air Feed Feed concentration (T out ) Collection vessel Side 11

12 Effect of Spray Drying Parameters Particle size Feed concentration, Atomization ratio (Atom. gas flow rate/feed flow rate), Outlet temperature, Particle morphology, Nozzle type Volatile content Outlet temperature, Drying gas flow rate (residence time), Particle morphology, Particle size Particle morphology Solvent and carrier choice, Outlet temperature, Formulation Yield Particle size, Volatile content, Particle Morphology Side 12

13 Amorphous versus Crystalline - Definition Crystalline Amorphous the adjective, crystalline, implies an ideal crystal in which the structural units, termed unit cells, are repeated regularly and indefinitely in three dimensions in space Vippagunta et al, Advanced Drug Delivery Reviews, 48, 2001 Similar to a crystalline solid an amorphous solid may have short-range molecular order, but unlike a crystalline solid, an amorphous solid have no long-range order of molecular packing L. Yu., Advanced Drug Delivery Reviews, 48, 2001 Side 13

14 Amorphous versus Crystalline Positive Improved dissolution rate Bioavailability Negative Stability More hygroscopic Side 14

15 Physical Stability The glass transition temperature (Tg) is often used to predict stability As a rule of thumb Hancock et al. (1995) proposed that the Tg of a pharmaceutical product should be at least 50 ºC above the storage temperature Stabilization approaches are often necessary for amorphous pharmaceutical drugs Side 15

16 Physical Stability Moisture sorption Absorbed water act as plasticizer, increasing molecular mobility resulting in a reduced Tg Absorbed water can alter the hydrogen bonding between molecules Phase separation often accompanied with re-crystallization Side 16

17 Stabilization - Solid Dispersions Several studies have shown the potential of high Tg polymers to inhibit/retard re-crystallization of amorphous drugs Mechanisms Anti-plasticizing effect Interactions between drug and polymer Enchanged solubility Side 17

18 Specific Study Side 18

19 Purpose To increase the dissolution rate of Tolfenamic acid through manipulation of solid state properties The intension is to produce small amorphous particles prepared by spray drying method Stabilization of this high-energy amorphous form by addition of crystal growth inhibiting compounds Side 19

20 The Drug Tolfenamic Acid NSAID White and yellow polymorph (conformational geometry of amino group) Hydrogen bonded dimers in crystal Yellow polymorph Comparable solubility Solubility in water: ~ 50 µg/ml Solubility in ethanol: ~10 mg/ml Solutions of both modifications are colourless and have identical physical properties White polymorph Side 20

21 Preliminary Experiments Part 1: Composition of feed solution Screening of suitable excipients, primarily within the water soluble polymers Selection of drug/polymer ratios Selection of solvent for feed solution Concentration Choices: Formulation as solid dispersion with PVP as excipient Drug/polymer ratio: (1:1, 1:3, 1:5, 1:7) Ethanol as solvent Side 21

22 Preliminary Experiments Part 2: Optimization of the spray drying process (process parameters) Feed flow 20 g/min 16 g/l Feed Heater 115 º C 80 kg/hr Nozzle gas flow Drying chamb er 2 fluid nozzle 1 mm Cyclone 6 kg/hr Collection vessel Bag filter Exhaust air Side 22

23 Preparation & Characterization Solution Spray drying Solid particles Initial characterization Stability study Drug content Dissolution XRPD TGA SEM FTIR Side 23

24 Dissolution % Released Time(min) Spray dried TA Physical mixture 1:1 SD 1:1 SD 1:3 SD 1:5 SD 1:7 TA as obtained from supplier Side 24

25 Morphology, Crystallinity & Stabilization θ (degrees) 2θ (degrees) θ (degrees) θ (degrees) SD 1:1 12 weeks 10 SD 1:1 24 weeks Side 25

26 Stability - Interaction Weight loss (%) Measured Additive prediction Molar TA starting excess material PVP prediction Physical mixture 1: SD1:1 SD1:3 SD1:5 SD1:7 % PVP Measured after 12 weeks storage equilibrium reached Side 26

27 Main Conclusions from Study - Summery Able to transform tolfenamic acid into its amorphous form in solid dispersions All solid dispersions show higher dissolution rate when compared to physical mixture and starting material The drug to polymer ratio is important from a stability point of view Indication of intermolecular interaction in the solid dispersions Side 27

28 More Interested.. The presented data is included in a paper accepted for publication in Pharmaceutical Development and Technology (January 2007). Side 28

29 Acknowledgments Lars Hovgaard, DUPS (main supervisor) Flemming Hansen, University of Copenhagen (XRPD) Sandoz (financial support) Drug Research Academy (financial support) Side 29