Excipient Composition and Performance-Related Properties of Excipients Chris Moreton, Ph.D. FinnBrit Consulting IPEC-Americas FDA Seminar, October 21,

Presentation Outline How excipient performance arises Excipient composition Excipient form Excipient performance examples 2

Excipient Performance Most often we do not know just what correlates with the performance of an excipient in a particular application (formulation). What we can say is that performance must arise from a combination of: – The chemical composition of the excipient The chemical nature of the nominal excipient The composition profile of the excipient – Including concomitant components! Molecular weight distribution for polymers – The physical properties of the excipient – The physical form of the excipient Excipient performance will change with the application (formulation). 3

Excipient Composition What are excipients comprised of? – The nominal excipient – What else? It depends! – The source of the raw materials (feedstock) – How the excipient is manufactured – How the excipient is processed – Are there any additives? 4

Excipient Manufacturing: Sources of Excipient Components 1.Concomitant components 2.Residual solvents 3.Residual catalysts 4.By-products Processing steps Final isolation Packaged Excipient Processing aid Additives Starting material(s) (Feedstock) Co-processing component Finishing 1.Residual solvents Bulk finished excipient Excipient composition 1.‘Nominal’ component(s) 2. Additive(s) 3. Processing aid(s) 4. Concomitant components 5. Residual processing aids 6. Residual solvents 7. Residual catalysts 8. By products 9. Unreacted starting materials 10. Starting material components Co-processing component 1.Concomitant components 2.Unreacted starting material 3.Other components from starting materials 4.Starting material impurities 5

Chemical Composition of the Excipient Nominal chemical – Polymer molecular weight distribution Concomitant components – Reaction by-products – Residual starting materials and reagents – Processing aids Undesirable components – Potentially toxic components, e.g. monomer residues in some polymers Residual solvents Elemental residues Water Additives 6

Physical Properties of the Excipient Molecular properties – UV absorption – Optical rotation Aggregate properties (molecular interactions) – Melting behavior Bulk properties – Powder flow – Bulk and tapped densities 7

The Physical Form of the Excipient Polymorphism Particle size distribution Particle morphology – Needle crystals – Plate crystals – Dendritic crystals Particle structure – Total surface area vs. ‘envelope’ surface area 8

Challenges in understanding the link between Excipient Composition and Excipient Performance We know what we know. BUT we do not know how much we don’t know! We can see the effects of poor understanding in failed product batches: – But is it the API, the excipient, the process or a combination of them? We can sometimes link poor performance to a particular material attribute, but only for a specific application: – We do not have a universal understanding of the link between excipient composition and performance. Is there one? We frequently do not properly understand what we need to measure, and we very often do not have adequate methods with which to measure. 9

Excipient Performance Since excipient performance will vary from application to application, it follows that we can only truly assess performance in the actual application (formulation). We need surrogates for excipient performance: – USP-NF Excipient Performance – Ph.Eur – Functionality-related Characteristics 10

Examples 1.Microcrystalline Cellulose 2.Dibasic Calcium Phosphate, Dihydrate 11

Cellulose structure Courtesy JRS 12

Microcrystalline Cellulose Courtesy JRS Pharma 13

Microcrystalline Cellulose Microcrystalline cellulose (MCC) contains: – Cellulose-I (  -cellulose) – Cellulose-II (β-cellulose) – Hemicelluloses – Ammonia residues – Formic acid/formaldehyde – Sugar residues (intrinsic aldehyde type reactions) Very ‘pure’  -cellulose does not perform as well as MCC BUT what are the components to control? What method(s)? 14

MAIN GRADES OF MICROCRYSTALLINE CELLULOSE Grade Size Characteristics PH 101ca. 50 µm PH 102ca. 90 µm PH 103ca. 50 µmMoisture content < 3% PH 105< 20 µm PH 112ca. 90 µmMoisture content < 1.5% PH 113ca. 50 µmMoisture content < 1.5% PH 200ca. 180 µm PH 200 LMca. 180 μmMoisture content < 3% PH 301ca. 50 µmHigher density PH 302ca. 80 µmHigher density Ceolus KG 802ca. 50 µmLower density Ceolus UF 711ca. 50 μmLower density, better flow Ceolus KG 1000ca. 50 μmVery low density 15

Dibasic Calcium Phosphate Dihydrate CaHPO 4.2H 2 O (DCP-D) Deforms during tablet manufacture by fragmentation (brittle fracture) We can make very pure DCP-D using precipitated calcium carbonate and so-called ‘ green ’ phosphoric acid. This very pure material does not perform well in compaction. The fragmentation appears to be due to dislocations in the DCP-D crystal lattice from the presence of foreign cations. The very ‘ pure ’ DCP-D appears not to have sufficient lattice dislocations, and thus does not fragment adequately to make strong enough compacts. 16

Dibasic Calcium Phosphate Dihydrate So what do we need to control? Do we have the methods? Could this conflict with the proposed limits for elemental impurities? 17

Additives in Excipients There is a lot of misunderstanding in the area: – There are additives that have been present for many years, but have not been declared: Excipient manufacturers have been unaware of the requirements of USP-NF General Notices Intellectual property issues surrounding additives. – We need to be careful we do not inadvertently cause excipient manufacturers to withdraw from servicing the pharmaceutical sector. – Some so-called ‘additives’ are actually processing aids carried over from earlier stages in the processing or extraction of the excipient. – IPEC-Americas has an active project in this area, and will be requesting a meeting with the FDA in 2014 to suggest a possible resolution. 18

Conclusions We do not know enough about any excipient to state that we completely understand the link between excipient composition and form, and the performance of that excipient across different applications. Performance related surrogates will need to be specified on a case by case basis. – Between the User and the supplier. Excipient composition will continue to be an issue. Communication and acceptance of Additives in excipients is an issue that needs to be resolved. 19