Understanding the Physics and Chemistry of Drug Stability

This course will be held on 26 and 27 April 2010 at the Regardz Berghotel, Amersfoort, the Netherlands.

Course Introduction and Aims

Drug Stability: Scientific Principles
Stability as a concept frequently appears in the pharmaceutical literature and in legal and regulatory documents. The nine modules which compose this course treat the physical and chemical stability of solid pharmaceutical and biopharmaceutical molecules in their isolated states (API) and in their formulated preparations. Emphasis is placed on stability changes that invariably accompany or result from physical and/or chemical changes during manufacture and thereafter.

Since biopharmaceutical products, as used, are generally amorphous (i.e. non-crystalline), their physical and chemical stability must be expresses in terms of the appropriate materials science of such non-equilibrium states, which always contain water as a component.

Analytical techniques suitable for the study of slow changes in physical and chemical properties are reviewed, and their respective suitabilities for a useful characterisation of attributes like ‘state’ and ‘shelf-life’ are assessed.

Who should attend

The course is designed primarily for pharmaceutical technologists, chemists, material scientists and engineers who are involved in the downstream processing, purification, drying, post-drying treatments and analysis of solid drug materials and their long-term stability assessment. Attendance will also be useful for those whose concerns are IP filing and litigation and regulation concerns. A basic knowledge of the relevant scientific principles involved (physics, physical and analytical chemistry) will be a distinct advantage. Graduate students of the relevant subjects, who are planning to enter the pharmaceutical industry, will also be welcome.

The Modules

Physical Stability of API and excipients

1. Structural and dynamic features of the different phases of a compound
   • Disorder in crystalline and amorphous molecular compounds.
   • Different aspects of molecular mobility in pharmaceuticals.
   • Experimental observation of disorder and molecular mobility.
2. Stability Criteria of pharmaceutical solids
   • Polymorphism and metastability: the different situations found in pharmaceutical solids. Phase diagrams.
   • How to estimate and measure stability differences.
   • Effect of polymorphism on product quality and performance: Solubility, reactivity, manufacturability.
   • Experimental observation of polymorphism in drugs. Case studies.
3. Kinetics of phase transformations and crystallization
   • Factors which influence the transformations between states and their rates.
   • Mechanisms of transformations in pure and mixed pharmaceuticals.
   • Factors involved in the ability to crystallise a pharmaceutical product.
   • Practical limits for undercooling and supersaturation: Crystal/Glass alternatives.
   • Phase separation/non-separation alternative.
   • Experimental techniques for observations of the transformations.
4. Amorphous and glassy drugs
   • Glass transition: experimental signatures.
   • Specificities of transport coefficients and molecular mobility. Fragility.
   • Methods to characterize the amorphous state and estimate the amorphous rates.
   • Molecular Mobility in the glassy state and its link with stability.
   • Preparation and aging of amorphous materials. Polyamorphism.
   • Manipulation of glass properties and possibilities of stabilisation. State diagrams.
5. Influence of formulation on the physical state
   • Transformation of pharmaceuticals induced by milling.
   • Transformations induced by desolvatation.
   • Involvement of the particle size on the physical states and their evolutions.
   • Sintering.

Chemical stability of API, excipients and formulated preparations

1. Origins of chemical instability
   • Complexities of API molecules – small molecules vs. biopolymers; neutral vs. ionic
   • Thermal and photostability.
   • Aqueous solutions – types of destabilising reactions involving water.
   • Special case: protein conformational stability issues.
2. Destabilising effects during drying (solidification)
   • Saturation and supersaturation.
   • Crystallisation vs. vitrification; control by choice of excipients.
   • Stability of formulated preparations.
   • Influence of drying parameters (temperature, pressure, time) on final stability and on reconstitution.
3. Excipients that provide acceptable stability
   • Requirements for formulation additives, their effects on stability.
   • Chemical stabilisation reactions, e.g. PEGylation.
   • Essential/unique features of carbohydrate excipients C_n(H₂O)_m e.g. microheterogeneity in aqueous media; chemical reactions in aqueous glasses.
   • Control of residual water content and its effect on product shelf life.
4. Stability monitoring of solid pharmaceuticals
   • Thermal techniques - scanning and isothermal.
   • Spectroscopy.
   • Scattering of radiation (light, X-rays, neutrons).
   • Biochemical methods.
   • Accelerated vs. real time methods.
   • Case studies.