Pharmaceutical Spray Drying (Upperton)

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Pharmaceutical Spray Drying (Upperton)

  1. 1. Pharmaceutical Spray Drying Dr Richard Johnson 12th May 2010
  2. 2. Dr Richard Johnson <ul><li>Founding Director of Upperton Limited </li></ul><ul><ul><li>Using spray drying to formulate API’s and biotechnology products </li></ul></ul>
  3. 3. Presentation <ul><li>Upperton spray drying service </li></ul><ul><li>Spray drying: basic principles </li></ul><ul><li>Applications in pharmaceutical/biotech formulation </li></ul>
  4. 4. Upperton Spray Drying Service 12th May 2010
  5. 5. Upperton background <ul><li>Founded in 1999 </li></ul><ul><li>Based in Nottingham, UK. </li></ul><ul><ul><li>R&D laboratories, Crocus St, central Nottingham </li></ul></ul><ul><ul><li>cGMP spray drying at R5 Pharmaceuticals, BioCity, Nottingham </li></ul></ul><ul><li>Over 18 years experience in spray drying and other particle technologies </li></ul>
  6. 6. Upperton spray drying service <ul><li>Work with customers to exploit the benefits of spray drying in the formulation of our clients products </li></ul><ul><li>Offer a research and development service from concept through to cGMP manufacture </li></ul><ul><li>Range of spray drying options </li></ul><ul><ul><li>Buchi B-290 </li></ul></ul><ul><ul><ul><li>100mg to 100g spray dried product </li></ul></ul></ul><ul><ul><li>Niro Mobile Minor (pharmaceutical design) </li></ul></ul><ul><ul><ul><li>based at R5 Pharmaceuticals </li></ul></ul></ul><ul><ul><ul><li>100g to 10kg spray dried product </li></ul></ul></ul>
  7. 7. Spray Drying Basic Principles
  8. 8. FROM LIQUID TO POWDER…IN SECONDS
  9. 9. Basic principles of spray drying <ul><li>Simple process, developed for the food industry </li></ul><ul><ul><li>spray dried egg, milk etc </li></ul></ul><ul><li>Liquid feed (solution or suspension) containing compound(s) of interest </li></ul><ul><li>Atomisation of liquid feed into a continuous (heated) stream of drying air/gas </li></ul><ul><ul><li>liquid phase evaporates, leaving dry powder carried in drying air stream </li></ul></ul><ul><li>Dry powder continually collected from heated air stream </li></ul><ul><ul><li>continuous process </li></ul></ul>
  10. 10. Basic principles of spray drying
  11. 11. Control of particle size
  12. 12. Highly reproducible process
  13. 13. Basic principles of spray drying <ul><li>Drying step is rapid </li></ul><ul><ul><li>producing powders that are primarily amorphous in nature </li></ul></ul><ul><li>Gentle drying process </li></ul><ul><ul><li>possible to spray dry temperature sensitive molecules (e.g. antibodies) </li></ul></ul><ul><li>Solutions containing a mixtures of solids can be spray dried </li></ul><ul><ul><li>dried solids will inter-disperse to produce a “solid-solution” </li></ul></ul><ul><ul><ul><li>enhanced stability </li></ul></ul></ul><ul><ul><ul><li>increase bioavailability </li></ul></ul></ul><ul><li>Suspensions can also be spray dried </li></ul><ul><ul><li>potential to encapsulate materials </li></ul></ul>
  14. 14. Advantages over other drying technologies <ul><li>Scale/cost </li></ul><ul><ul><li>from less than a gram to several hundred kilograms </li></ul></ul><ul><ul><li>cost-effective compared to other processes (e.g. freeze drying) </li></ul></ul><ul><ul><li>continuous, highly-reproducible process </li></ul></ul><ul><li>Speed of drying </li></ul><ul><ul><li>rapid processing promotes the formation of amorphous powders, with subsequently improved stability/bioavailability </li></ul></ul><ul><li>Ability to produce discreet particles </li></ul><ul><ul><li>improved powder handling properties compared to other drying techniques </li></ul></ul><ul><ul><li>ability to target based on particle size </li></ul></ul>
  15. 15. Pharmaceutical Applications of Spray Drying
  16. 16. Pharmaceutical Applications <ul><li>Simple drying technique </li></ul><ul><ul><li>evaporating liquid to produce dry powder form to enhance stability, aid further processing </li></ul></ul><ul><li>Stabilising peptides, proteins and antibodies </li></ul><ul><ul><li>dry powder formulations with enhanced storage stability </li></ul></ul><ul><li>Particle engineering </li></ul><ul><ul><li>formulating drugs in a discreet particle to improve delivery </li></ul></ul><ul><li>Enhance bioavailability </li></ul><ul><ul><li>to enhance dispersion/dissolution of poorly soluble drugs, resulting to improved bioavailability </li></ul></ul>
  17. 17. <ul><li>Aqueous solution of recombinant protein (60kDa) with potential to polymerise on spray drying/storage </li></ul><ul><ul><li>di-sulphide bond re-arrangement </li></ul></ul><ul><ul><li>-amino- carboxyl groups on amino acid side chains can react (dimer/polymer formation) </li></ul></ul><ul><li>Initial research focused on effect of drying temperature </li></ul><ul><ul><li>50-80 º C optimal to retain activity </li></ul></ul><ul><ul><li>moisture content of powder typically in 3-6% (w/w) range </li></ul></ul><ul><li>Spray dry at solids content of 5-10%(w/v) found to give optimal yield </li></ul><ul><ul><li>balance viscosity against processing times/cost </li></ul></ul>Example 1: Stabilising peptides and proteins
  18. 18. <ul><li>When spray dried without excipients, protein was prone to aggregation (particularly on storage) </li></ul><ul><ul><li>significant amount of polymer after 4 weeks storage at 40 º C </li></ul></ul><ul><li>Addition of stabilising excipient (trehalose) resulted in significant reduction in polymerisation events </li></ul><ul><ul><li>100% monomer retained after 4 weeks storage at 40 º C </li></ul></ul>Example 1 : Stabilising peptides and proteins
  19. 19. Example 1 : Stabilising peptides and proteins Pre-spray drying 1 2 spray dried t=28d 3 4 1 spray dried t=0 2 3 spray dried (50% trehalose) t=0 4 spray dried (50% trehalose) t=28d
  20. 20. <ul><li>Small (1-3µm) particles required for inhaled delivery application </li></ul><ul><ul><li>delivery of MRI contrast agent into deep lung (alveoli) </li></ul></ul><ul><li>Spray dry aqueous solution in in 2-5% (w/v) range </li></ul><ul><ul><li>reduced solids content will produce smaller dry powder particles </li></ul></ul><ul><li>Atomisation air flow/pressure will also impact on particle size </li></ul><ul><ul><li>use higher air flow/pressure to produce smaller liquid droplets (leading to smaller particles) </li></ul></ul><ul><li>Addition of water-miscible solvents to reduce viscosity further resulted in even smaller particles </li></ul>Example 2: Particle engineering
  21. 21. Inhaled MRI contrast agent
  22. 22. Control of particle size (MRI contrast agent)
  23. 23. <ul><li>Aim: to enhance the solubility/bioavailability of drug that is poorly soluble in water </li></ul><ul><li>Produce a spray dried dispersion (SDD) of drug in polymer matrix </li></ul><ul><ul><li>polymers are routinely used, eg Povidone, Hydroxypropyl methylcellulose </li></ul></ul><ul><ul><li>spray dry organic solvent containing solution of drug:polymer </li></ul></ul><ul><ul><li>result is a solid dispersion of drug in polymer matrix </li></ul></ul><ul><ul><li>both drug and polymer are in amorphous state </li></ul></ul><ul><li>SDD enhance drug bioavailability in aqueous environment </li></ul><ul><ul><li>polymer dissolves and drug dispersed into aqueous environment </li></ul></ul><ul><ul><li>increase drug surface area (range of nano-complexes) leading to enhanced bioavailability </li></ul></ul><ul><ul><li>polymer enhances stability of drug in the amorphous form </li></ul></ul>Example 3: Enhanced bioavailability
  24. 24. Amorphous Spray Dried Dispersion (SDD) drug/polymer solution spray dry spray dried dispersion of drug in polymer (SDD) prepare solution drug Solvent polymer
  25. 25. <ul><li>Drug has poor aqueous solubility, poor bioavailability </li></ul><ul><ul><li>Tg 29 °C (poor stability profile in amorphous state) </li></ul></ul><ul><li>Drug dissolved in organic solvent with hydroxypropyl methylcellulose acetate succinate (HPMCAS) </li></ul><ul><ul><li>polymer has both hydrophillic and hydrophobic regions, high Tg 119 ° C, </li></ul></ul><ul><li>Spray dried to produce SDD </li></ul><ul><ul><li>dry powder containing drug:polymer ratio 25:75 </li></ul></ul><ul><ul><li>drug dispersed uniformly with polymer, intermediate Tg 82 ° C </li></ul></ul><ul><ul><li>drug and polymer in amorphous state (stable) </li></ul></ul><ul><li>On aqueous dissolution drug interacts with polymer to yield nanostructure with enhanced bioavailability </li></ul><ul><li>* Friesen et al 2008 </li></ul>Example: Spray dried torcetrapib*
  26. 26. <ul><li>(1) torcetrapib (2) 25% torcetrapib, HPMCAS SDD </li></ul><ul><li>* Friesen et al 2008 </li></ul>Solubility of SDD torcetrapib*
  27. 27. <ul><li>* Friesen et al 2008 </li></ul>Bioavailability of SDD torcetrapib*
  28. 28. Conclusions
  29. 29. Spray drying: Conclusions <ul><li>Spray drying is a cost-effective technique for producing large quantities of dry powder from a solution/suspension </li></ul><ul><li>Relatively gentle drying process, capable of handling temperature-sensitive molecules </li></ul><ul><ul><li>addition of formulation excipients (such as trehalose) can further enhance storage stability </li></ul></ul><ul><li>Highly-reproducible technique capable of producing particles of defined size/morphology </li></ul>
  30. 30. Spray drying: Conclusions (II) <ul><li>Spray drying can provide a formulation solution for difficult to handle API’s </li></ul><ul><ul><li>Production of dry powders from solutions/suspensions </li></ul></ul><ul><ul><ul><li>aid processing, improve stability </li></ul></ul></ul><ul><ul><li>Enhance storage stability of proteins/peptides </li></ul></ul><ul><ul><ul><li>include the addition of stabilising excipients (e.g. trehalose) </li></ul></ul></ul><ul><ul><li>Excellent technique for producing particles of defined size </li></ul></ul><ul><ul><ul><li>nasal, pulmonary and intravenous delivery </li></ul></ul></ul><ul><ul><li>Enhance bioavailability of poorly-soluble compounds </li></ul></ul><ul><ul><ul><li>SDD of drug/polymer shows significant improvements in solubility and bioavailabilty </li></ul></ul></ul>

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