1. Drying in the Pharmaceutical Industry1 DIT- Msc Pharmaceutical and Chemical Processes Technologies 28 th April 2009 Sara Baeza

2. Drying in the Pharmaceutical Industry2 Agenda Introduction to Drying in the Pharmaceutical Industry. Introduction to the Drying process. Dyers selection for a Pharmaceutical process. Case Study: Trouble shouting the drying step and its impact on formulation.

3. Drying in the Pharmaceutical Industry3 Introduction Drying in Pharmaceutical Industry Drying APIs is an important operation for the production of consistent, stable, free-flowing materials for formulation, packaging, storage and transport Particle attrition or agglomeration can result in major differences in particle size distribution (PSD), compressibility and flow characteristics Equipment selection Drying specifications

4. Drying in the Pharmaceutical Industry4 Introduction to Drying Process  Drying can be described by three processes operating simultaneously: 1. Energy transfer from an external source to the water or organic solvent  Direct or Indirect Heat Transfer 2. Phase transformation of water/solvent from a liquid- like state to a vapour state  Mass Transfer (solid characteristics) 3. Transfer vapour generated away from the API and out of the drying equipment

5. Drying in the Pharmaceutical Industry5 Introduction to Drying Process(contd) Warm up period :A-B Constant Rate Period (B-C)  HT dependent Falling rate period (C-D)  MT dependent Periods of Drying Critical Moisture content

6. Drying in the Pharmaceutical Industry6 Dryers in the Pharma Industry  Dryers can be classified according to: Heat transferring methods  Direct: Fluidised, Tray, Spray, Rotary Dryers, etc..  Indirect: Cone, Tumble, Pan Dryers, etc… Continuous/ Batch processing  Continuous: large quantities/small residence time  Batch: small quantities/ long residence time Method of handling the solids.

7. Drying in the Pharmaceutical Industry7 Dryers in the Pharma Industry Dryers classification  Material Handling- API physical characteristics Flowability:  Charging/discharging of product Attrition/agglomeration  Control PSD and its impact on formulation Bulk density  Batch size Temperature stability  Melting point  Friction (agitator/discharging)  Polymorphic shifts Containment  Isolation & Drying equipment combined  Glove box

8. Drying in the Pharmaceutical Industry8 Case Study - Background Expand/back up dryer capability for API process Past development work concluded that API dried in high shear dryers lead to crystal attrition which was shown to adversely affect the formulation process and thus the drug performance Limited low shear dryers (cone dryer) availability Excellent high shear (Filter & Pan) Dryers availability

9. Drying in the Pharmaceutical Industry9 Case study – Developmental work Characterization of attrition/agglomeration suffered by API in high shears dryers such as FDR and PDR Characterize particle size (PSD) during drying by tracking Lasentec profiles in the dryer with time Correlate the loss of drying (LOD) with PSD Effect of Dryer agitation on attrition/agglomeration Physical characteristics of API comparable to conical dried material

10. Drying in the Pharmaceutical Industry10 Lab size jacketed FDR Rosenmound with variable agitation to induce varying degree of breakage while monitoring attrition with Lasentec PSD for Conical dried material:  Mean sq wt range= 60-80  median no wt range= 10-20 Case study – Developmental work

11. Drying in the Pharmaceutical Industry11  Experiment 1: 1 kg of wet API Initial LOD 25% Jacket Tem @ 55C Total drying time 1 h Continuous agitation 50 rpm during the drying Case study – Developmental work

12. Drying in the Pharmaceutical Industry12 Case study – Developmental work Crystal breakage was observed during early stages of the drying No significant breakage was observed afterwards (LOD=2.5%) PSD not comparable to conical dryer material

13. Drying in the Pharmaceutical Industry13  Experiment 2: 1 kg of wet API Initial LOD 25% Jacket Tem @ 55C Total drying time 3 h Intermittent agitation at 50 rpm, intervals of 5 min, applied during the first 1 h (LOD=2.4 %) After 1h, continuous agitation at 50 rpm Case study – Developmental work

14. Drying in the Pharmaceutical Industry14 Case study – Developmental work Crystal breakage was observed during early stages of the drying No significant breakage was observed afterwards

15. Drying in the Pharmaceutical Industry15  Experiment 3: 1 kg of wet API Initial LOD 25% Jacket Tem @ 55C Total drying time 4.5 h No agitation during first 1.5 h (LOD = 4 %) After 1.5 h, intermittent agitation at 50 rpm for 10 min every 10 min Case study – Developmental work

16. Drying in the Pharmaceutical Industry16 Case study – Developmental work Small crystal breakage was observed during early stages of the drying No significant breakage was observed afterwards

17. Drying in the Pharmaceutical Industry17  Experiment 4: 1 kg of wet API Initial LOD 25% Jacket Tem @ 55C Total drying time 5.5 h No agitation during first two hours (2.5 %LOD) After two hours, intermittent agitation at 5 rpm for 6 min every hour Case study – Developmental work

18. Drying in the Pharmaceutical Industry18 Case study – Developmental work No crystal breakage was observed during early stages of the drying No significant breakage was observed afterwards

19. Drying in the Pharmaceutical Industry19 Case Study Developmental work conclusions

20. Drying in the Pharmaceutical Industry20 Case Study Developmental work conclusions  FDR experiments produced comparable PSD material to conical dried material  The more rapid and aggressive agitation corresponded directly to an increased amount of attrition in the filter dried product  Particle breakage occurred in the early stages if the drying and was minimal in the late stages of the drying (wetness dependent)

21. Drying in the Pharmaceutical Industry21 Case Study Follow up  Conservative drying regime for manufacturing FDR was designed and scaled up based on the developmental experiments results obtained in lab FDR  Trial batch produced material that preformed successfully in the formulation site  Drying regime optimization and implementation currently on going

22. Drying in the Pharmaceutical Industry22 Q&A

23. Drying in the Pharmaceutical Industry23 References  http://pubs.acs.org/doi/pdf/10.1021/op05 0091q http://pubs.acs.org/doi/pdf/10.1021/op05 0091q  http://books.google.co.uk http://books.google.co.uk