Critical material properties for the design of robust drug products : excipient functionality related characteristics Dr Liz Meehan, Pharmaceutical Development, Macclesfield UK 1
Excipients Definition 1 : any substance other than the pharmacologically active drug or prodrug that is included in the manufacturing process or is contained in a finished pharmaceutical dosage form Excipients are increasingly being recognised for the critical role they play in pharmaceutical products. Pharmaceutical excipients contribute enormously to the efficacy of a product by providing specific special functionalities in formulations. 2 1. International Pharmaceutical Excipients Council-Americas, What are Pharmaceutical Excipients? http://www.ipecamericas.org/public/faqs.html#question1 2. Dr Fred Heinze, National Starch, Business Briefing : Pharmtech 2003, http://www.touchbriefings.com/pdf/17/pt031_t_natstar.pdf 2
QbD drivers for excipients Increased understanding of the role of excipients in the formulation and the process Science and risk-based approach to excipient selection (compatibility and functionality) Improved characterisation of excipients (material science) Clear understanding of how excipient variability can be tolerated by the process, still ensuring predictable, high quality, reproducible, stable product Defined analytical tools to assess the impact of excipient variability on formulation, process and product performance 3
Excipient functionality related characteristics (ERFC s) Compendial monographs primarily focus on purity and safety EFRC s are characteristics that are recognised as being important for the function of the excipient Functionality can only be properly assessed in the context of a particular formulation and manufacturing process 1 Impossible to establish widely accepted standards for functionality in a monograph for excipients due to the fact that the functionality is most likely related to a specific formulation and process Some evidence of non-mandatory EFRC s included in EP monographs and in USP general chapters for certain classes of materials 1. Excipient Functionality, R. C. Moreton, Pharmaceutical Technology, May 2004 4
Examples of EFRC s QbD concepts emphasize the need for characterizing material properties (e.g. micromeritic, chemical, thermal, rheological, and mechanical properties) and elucidate their vital role in formulation and manufacturing processes Particle shape, size and size distribution Type and degree of substitution Flowability Crystallinity Glass transition/melt temperature Molecular weight distribution Compressability 5
Polymeric excipients in pharmaceutical dosage forms Solubility enhancement Tablets Fillers Binders Disintegrants Coatings Release controlling Solid dispersions Lipid matrices Complexes Surfactants Parenterals Solutions Suspensions Liquid depots Gels Microparticles Solid depots 6
Polymeric excipients Polymers are inherently heterogeneous materials : MWD crosslinking CCD FTD As well as... Particle shape, size and size distribution Powder flow Compaction properties Crystallinity Moisture content 7
Case study : Hydroxypropylmethyl cellulose (HPMC, Hypromellose) Has many potenital functions in drug products : suspension stabiliser, binder for wet granulation, tablet coating, rate controlling excipient in extended release tablets Potential FRC s : MWD Degree of hydroxypropyl and methoxy substitution USP2208 grades: nominally 22% MeO, 8% HP subsitution Particle size 8
HPMC in hydrophilic matrix tablets for extended release In contact with gastric fluids the polymer swells to form a protective gel layer around the tablet Drug may be released by diffusion through this gel layer Drug is also released as the polymer gel layer erodes (polymer dissolves) The rate of diffusion and erosion is controlled by the properties of the hydrophilic polymer and the tablet formulation Typically tablet contains a minimum of 30% by weight of the release controlling polymer 9
Understanding the functionality of HPMC in a hydrophilic matrix tablet In-vitro dissolution testing of (extended release) tablets is a primary indicator of product performance Drug concentration determined by UV Polymer concentration (and intrinsic viscosity, IV) determined by Rapid Size Exclusion Chromatography 10
Polymer release from tablets as f(mw) % HPMC 120.00 100.00 80.00 60.00 40.00 20.00 0.00 0 5 10 15 20 25 30 time (hr) All USP2208 materials Nominal viscosity grades: 100mPa.s 100cP/4000mPa.s 4000mPa.s 15000mPa.s Body of tablet Dissolution medium Chain disentanglement is slower for higher molecular weight polymers (increased chain length) so the rate of polymer erosion is reduced 11
What about chemical composition? USP2208 grade polymers same viscosity grade (100mPa.s) but varying HP content 120 100 Ba 2 HPO: 12.1% MeO: 25.5% % released 80 60 HP: 12.0% MeO: 25.5% HP: 7.8% MeO: 25.9% Ba 1 HPO: 7.8% MeO 25.9% 40 20 0 0 10 20 30 40 50 60 Time (h) (h) 12
Mechanism for control of drug release? Diffusion : A strong, thick gel layer surrounds the tablet core so the drug dissolves quicker than polymer because it can diffuse through the gel layer Erosion : Polymer and drug erode (dissolve) from the tablet surface at roughly the same rate Typical erosion control Typical diffusion control USP 2208 100cP USP 2208 4000cP 120.00 Formulation 1 in ph6.8 +0.2% CTAB dissolution HPMC Active 120.00 Formulation 3 in ph6.8 +0.2% CTAB dissolution Active HPMC % dissolution 100.00 80.00 60.00 40.00 20.00 % dissolution 100.00 80.00 60.00 40.00 20.00 0.00 0 5 10 15 20 25 Time (hrs) 0.00 0 5 10 15 20 25 30 Time (hrs) 13
Case study : superdisintegrants Sodium starch glycolate (SSG) Chemically modified and crosslinked starch Croscarmellose sodium (CCS) Chemically modified and crosslinked cellulose Low substituted HPC (L-HPC) Chemically modified cellulose, no crosslinking Crospovidone Crosslinked synthetic polymer 14
Disintegrant functionality There is generally a lack of a precise understanding of the mechanism of disintegrant activity Several mechanisms of disintegrant action are reported in the literature wicking and capillary action swelling deformation recovery repulsion heat of wetting Proposed EFRC s Particle size and shape Chemical composition Degree of crosslinking However, no single mechanism is applicable to all disintegrant types and it is likely that in most cases a combination of mechanisms is taking place simultaneously The extent to which any of these mechanisms occur varies from disintegrant-to-disintegrant type and may also vary supplier-to-supplier within disintegrant type 15
Particle morphology SSG CCS Crospovidone L-HPC 16
Particle size distribution (1) Crospovidone Plasdone XL Plasdone XL10 Kollidon CL Kollidon CL-F L-HPC LH22 LH21 17
Particle size distribution (2) SSG Explotab Explotab CLV Primogel Glycolys LV CCS Primellose AcDiSol 18
Degree of swelling Settling volume at 24hr (degree of swelling) In water In 0.1N HCl 45 40 Settling volume (ml) 35 30 25 20 15 10 5 0 Kollidon CL Kollidon CL-F Polyplasdone XL Polyplasdone XL 10 L-HPC (LH-21) L-HPC (LH-22) Explotab Explotab CLV Primojel Glycolys LV Ac-Di-Sol Primellose Crospovidone L-HPC SSG CCS Determined by a simple functionality test, settling volume after 24 hours, which is included in the monograph of croscarmellose sodium (USP24NF19), but it is not a requirement for the other three disintegrants 19
Degree of cross-linking/soluble fraction Measure viscosity of a slurry of disintegrant in water over time, if soluble polymer is present then viscosity will increase SSG SSG LV others 20
Potential FRC s for disintegrants FRC/disintegrant SSG CCS Crospovidone L-HPC Particle size and shape Particle porosity Chemical composition Degree of cross linking 21
Summary EFRC s in QbD Functionality of excipients exists only in the context of a specific formulation Lot-to-lot variability of excipients is to be expected, therefore formulations and processes need to be designed accordingly Identify potential FRC s for excipients in a formulation Develop suitable characterisation methods to measure the properties of key excipients Assess the degree of variability of those excipient properties Develop a library of materials, accompanied by a database of characterisation data Using a Design of Experiments approach, model the impact of excipient variability on product performance, processability and stability and develop an appropriate control strategy 22
Further reading Debating excipient functionality, M Rios, Pharmaceutical Technology, September 2006 Excipient Functionality, R. C. Moreton, Pharmaceutical Technology, May 2004 Understanding critical material properties for solid dosage form design, A. J. Hlinak, K. Kuriyan, K. R. Morris, G. V. Reklatitis, P. K. Basu, Journal of Pharmaceutical Innovation, Sept/Oct 2006 23