Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Wa

1. Pharmaceutical Development Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Waterfront Cape Town, South Africa Date: 16 to 20 April 2007

2. Pharmaceutical Development Pre-Formulation and Formulation Development Presenter: Simon Mills Email: Simon.n.mills@gsk.com

3. Outline and Objectives of Presentation • Stress Testing of API • Impact on API Specifications • Pre-Formulation Investigations • Solid State Degradation • Role of Excipients in API Instability • Hydrolysis • Oxidation • Photolysis • Miscellaneous Degradation • Selection of Processing Method • Processing Strategies for Combination Products • Role of Processing in Product Instability

4. Stress Testing of API • Serves two purposes: • To evaluate the specificity of the ‘stability indicating’ method’, e.g. LC • To understand the degradation pathways of the API to facilitate rational product development • Hydrolysis, Oxidation, Photolysis and the role of pH • Initially performed overa short period of time (28-days) using accelerated or stress conditions (reactions proceed more rapidly under elevated temperatures) • Arrhenius Equation: K = Ae-EaRT • wherek is reaction rate constant, A is a constant (frequency factor), Ea is the activation energy of reaction, R is the gas constant and T is the temperature (in degrees Kelvin) • Typical conditions for API in solid state might be: • 80°/75%RH, 60°C/ambient RH, 40°/75%RH, • Light irradiation • Typical conditions for API in solution state might be: • pH 1-9 in buffered media (e.g. phosphate buffer), • with peroxide (and/or free radical initiator) • Light irradiation

5. Impact on API Specification • The allowable level of any given impurity or impurities that are permitted in API/drug product, without explicit non-clinical safety testing, are defined by ICH Q3A/B. • The amounts of impurities that are allowable are based on the total daily intake of the drug product. • There are separate limits (or thresholds) for reporting, identification and qualification of API impurities. • The reporting threshold is defined as the level that must be reported to regulatory agencies to alert them to the presence of a specified impurity. • The identification threshold is defined as the level that requires analytical identification of a specified impurity. • Finally, the qualification threshold is defined as the level where the specified impurity must be subjected to non-clinical toxicological testing to demonstrate safety. This threshold limit is defined as a percentage of the total daily intake of the drug product, or in absolute terms as the total allowable amount, whichever is lower.

6. API Impact on Specification

7. Excipients:API Interaction • Whereas excipients are usually biologically inactive, the same cannot be said from a chemical perspective. • Excipients, and the impurities present therein, can stabilise and/or destabilise drug products. • Before initiating drug product development, the formulation scientists must fully consider the chemical structure of the drug substance, the type of delivery system required, and the proposed manufacturing process. • Initial selection of excipients should be based on expert systems, appropriate delivery characteristics, personal choice and knowledge of potential mechanisms of degradation for the drug in question. • Known chemical incompatibilities of common excipients may be obtained from existing published information, e.g. lactose with primary amines. • The objective of drug/excipient compatibility considerations and practical studies is to delineate, as quickly as possible, real and potential interactions between potential formulation excipients and the API. This is an important risk reduction exercise early in formulation development. How is it achieved?..........

8. Excipients Compatibility One option….Binary Mix Compatibility Testing: • In the typical drug/excipient compatibility testing program, binary (1:1 or customised) powder mixes are prepared by triturating API with the individual excipients. • These powder samples, usually with or without added water and occasionally compacted or prepared as slurries, are stored under accelerated conditions and analysed by stability-indicating methodology, e.g. HPLC, CE, etc. • (The water slurry approach allows the pH of the drug-excipient blend and the role of moisture to be investigated.) • However, this entire process takes time and resources and….it is well known that the chemical compatibility of an API in a binary mixture may differ completely from a multi-component prototype formulation.

9. Excipients Compatibility • Alternatively, binary samples can be screened using thermal methods, such as DSC/ITC. This alternative approach eliminates the necessity for stability set downs; hence cycle times and sample consumption are reduced. However, the data obtained are difficult to interpret and may be misleading; false positives and negatives are routinely encountered. Also sensitive to sample preparation. • An alternative is to test “prototype” formulations. The amount of API in the blend can be modified according to the anticipated drug-excipient ratio in the final compression blend. • Platform prototypes can be used for specific dosage forms, e.g. DC vs. wet gran tablets • There is better representation of likely formulation chemical and physical stability • However, a more complex system to interpret

10. Excipient Compatibility • Drug-excipient interactions can be studied using both approaches in a complementary fashion. The first tier approach is to conduct short-term (1-3m) stability studies using generic prototype formulations under stressed conditions, with binary systems as diagnostic back-up: • Chemical stability measured by chromatographic methods • Physical stability measured by microscopic, particle analysis, in vitro dissolution methods, etc. • The idea is to diagnose any observed incompatibility from the prototype formulation work then hopefully identify the “culprit” excipients from the binary mix data. • Hopefully, a prototype formulation can then be taken forward as a foundation for product development. • It is possible to apply statistical designs to determine the occurrence of chemical interactions in more complex systems such as prototype formulations, with a view towards establishing which excipients cause incompatibility within a given mixture.e.g. for a tablet product, a 25 factorial design, consisting of 4 wet granulation excipients (filler, lubricant, disintegrant and binder) and the fifth factor represented humidity, extensively encountered during the wet granulation process, can be used.

11. Solid State Degradation • The manner in which drugs degrade in solid oral dosage forms is still rather obscure, despite the best efforts of several eminent investigators in the field (12, 13). • The kinetics of the degradation reactions are difficult to interpret and the orders of the reaction are often complex. The following mechanisms have been proposed by Wells (14). (12). C. Ahlneck and G. Zografi, Int. J. Pharm., 62, (1990) 87. (13). J.T. Carstensen and T. Morris, J. Pharm. Sci., 82 (1993) 657. (14). J.I. Wells, Pharmaceutical Preformulation, Excipient Compatibility, Ellis Horwood, Chapter 8 (1987).

12. Solid State Degradation • Probably, the most important reaction mechanism is the liquid mediated process (iii). • This is because most drugs, even those not particularly susceptible to hydrolysis, become less stable as the surrounding moisture levels increase. • It has been speculated that degradation proceeds via a thin film of moisture on the surface of the drug substance. • However, studies have indicated that the moisture is concentrated in local regions of molecular disorder, rather than in thin films. These regions, which are crystal defects or amorphous areas, equate to the reaction nuclei of mechanisms (i) and (ii).

13. Solid State Degradation • It has been postulated that it is not necessary for the API to be dissolved, to induce degradation. • The proposal is that water adsorbed into regions of localised disorder can act as a plasticiser, lowering the glass transition temperature (Tg) of excipients and API, and so permitting increased local molecular movement can increase chemical reactivity. • In some cases, there has been shown to be a correlation between the reaction rates and Tg. This hypothesis supports the observation that even relatively low moisture levels can destabilise drug products. • Other research has indicated that the destabilising affect of small amounts of amorphous material in a crystalline matrix can be hugely amplified, as a result of local areas of greatly increased water content relative to total water content.

14. Solid State Degradation • It has been shown in a number of instances that under identical conditions, the reaction rates of amorphous solid-state forms are greater than in crystalline forms of the same drug. • Generally water has a destabilising effect in the majority of cases; e.g. moisture mediated deamidation, hydrolysis, or oxidation. • In summary, there are at least four ways in which residual moisture in the amorphous state can impact on chemical reactivity. • Firstly, as a direct interaction with the drug, for example, in various hydrolytic reactions. • Secondly, water can influence reactivity as a bi-product of the reaction, by inhibiting the rate of the forward reaction, for example, in various condensation reactions, such as the Maillard reaction. • Thirdly, water acting locally as a solvent or medium facilitating a reaction, without direct participation. • Finally, by virtue of its high free volume and low Tg, water can act as a plasticiser by reducing viscosity and enhancing diffusivity.

15. Excipients and API Incompatibility • Water can be associated with excipients in a number of very different ways: • as crystal hydrates, e.g. dicalcium phosphate dihydrate, lactose monohydrate • by absorption into the bulk phase of crystalline or amorphous solids • by adsorption onto a surface as a monolayer or multilayers, • by capillary condensation into micropores. • Callahan et al (24) divided excipients into four classes • non-hygroscopic (I) • slightly hygroscopic (II) • moderately hygroscopic (III) • very hygroscopic (IV). • The authors determined/categorised the equilibrium moisture values for 30 common excipients (24). J.C. Callahan, G.W. Cleary, M. Elefant, G. Kaplan T. Kensler and R.A.Nash, Drug Dev. Ind. Pharm., 8 (1982) 355.

16. Excipients and API Incompatibility Further theories of interaction: • In a closed system, water from excipients will re-equilibrate between the individual components of the formulation, via the vapour phase, to attain the most thermodynamically stable state. In practice, as most excipients contain more available moisture than the drug substance, this results in the API being the net recipient of the available moisture, resulting in an increased potential for degradation. • In the case of hydrophobic excipients, there is the potential for drug to be adsorbed onto the surface of the excipient, resulting in the formation of a drug mono-layer, which would be more susceptible to chemical instability.

17. Excipients and API Incompatibility • The degradation rate for many drugs varies as function of pH of the environment. • This appears to be equally true in the solid-state as it is in the solution-state. • pH within the micro environment of a solid oral dosage form can impact on the stability of the formulation, especially true for degradation which is pH sensitive. • Ahlneck and Lundgren (29) studied the compatibility of aspirin in the presence of 3 common diluents; • lactose • microcrystalline cellulose • dicalcium phosphate • The authors demonstrated that dicalcium phosphate despite having much lower moisture pick up levels than microcrystalline cellulose, had a greater de-stabilising effect. • Attributed to the alkalinity of the dicalcium phosphate in the solid state (pH 7.4). The increase in the pH adversely affects the stability of the formulation, despite minimal solubility in water. (29). C. Ahlneck and P. Lundgren, Acta Pharm. Suec., 22 (1985) 305

18. Hydrolysis and the Role of Excipients • One of the most common pathways of drug product degradation is hydrolysis. • Flutamide, a non-steroidal anti-androgen, is an acetanilide derivative and undergoes acid and base catalysed amide hydrolysis (43), at the extremes of pH to form 4-nitro-3-trifluoromethylaniline (NTMA). • Solutions of flutamide stored at pH 1 for 2 weeks at 45C gave 39% of NTMA; whereas, solutions at pH 10 gave 21% of NTMA (same storage conditions). Neutral solutions of flutamide were stable (<0.4% NTMA). • The source of the excipients can greatly influence hydrolytic reactions. • This is exemplified by Gold and Campbell (44) where talc obtained from different sources impacts markedly on the overall stability of the aspirin tablet formulation. • This is possibly attributable to the affect of different types and amounts of surface impurities, which are dissolved in the adsorbed moisture layer, where they subsequently react with the API. It could also influence the pH of the micro-environment.

19. Oxidation and the Role of Excipients • Oxidation is broadly defined as a loss of electrons in a system, but it can be restated as an increase in oxygen or a decrease in hydrogen content. • Oxidation always occurs in tandem with reduction; the so called REDOX reaction couple. More generally, it can be defined as the loss of an electron positive atom, radical or electron, or the addition of an electronegative moiety. • Oxidation reactions can be catalysed heavy metals, light, leading to free radical formation (initiation). Free radicals then react with oxygen to form peroxy radicals, which react with the oxidative substrate to yield further complex radicals (propagation), finally the reaction ceases (termination). • Excipients play a key role in oxidation; either as a primary source of oxidants, trace amounts of metals, or other contaminants. • Peroxides are a very common impurity in many excipients, particularly polymeric excipients. They are used as initiators in polymerisation reactions, but are difficult to remove.

20. Photolysis and the Role of Excipients • Sunlight (both in the UV and visible regions) may degrade drug products and excipients; and consequently photolabile APIs can raise many formulation issues. • The addition of light absorbing agents is a well known approach to stabilising photolabile products. • E.g. it has been reported that the incorporation of light absorbers and pigments considerably improved the photostability of light sensitive molsidomine tablets. Pigments > colorants > UV absorbers • However, they warned that the use of titanium dioxide (an opacifier) needs to be considered carefully. Although, preblending of titanium dioxide with the drug compression blend was successful; surface-treated material, which according to Laden et al (51) reduces photocalalytic activity, was inferior to the untreated excipient.

21. Miscellaneous Degradation • Formation of a thioester (ethyl-2-mercaptoacetate) in heat stressed packaging material of a tablet product (53) • resulting from the unanticipated reaction • small levels of residual ethanol in the tablet disintegrant • low levels of thioglycollic acid* from pack * thioglycollic acid is an impurity of the organotin heat stabilising plastic additive (di-n-octyltin-bis [iso-octylthioglycollate]) in packaging material (53). Sides et al, J. Pharm. Biomed. Anal., 25 (2001) 379-386

22. Selection of Processing Methodology • Understanding of degradation pathways of API will help to decide on most appropriate process • For APIs showing severe moisture mediated degradation pathways, choose direct compression or dry granulation • Many ester pro-drugs are formulated in alcoholic and semi-solid vehicles to preclude (or reduce) hydrolysis • Understanding of physical properties of API will help to decide on most appropriate process • For APIs showing flow issues, choose a granulation approach (wet or dry granulation) • For APIs showing reduced crystallinity after processing e.g. milling, micronisation, etc., choose wet granulation (presence of water will anneal (crystallise) amorphous API) • For APIs with low melting point, choose an encapsulation approach (high speed rotary presses will generate significant frictional forces that could melt API)

23. Processing Methodologies For Combination Products • Objective is to minimise incompatibilities. Degradation pathways of the two APIs could well be different, so a stabilisation strategy for API #1 could destabilise API #2. • In this situation, first intent strategy could be to prepare separate compression blends of each individual API and compress as a bi-layer tablet • Disadvantages are that bi-layer rotary presses are more complex and expensive • Alternatively, could compress one of the APIs and over-encapsulate this into a capsule product, along with the powder blend from the second API • Disadvantage are that capsule size could be large (Supra A or larger), require specialised encapsulation equipment to fill tablets and blend… process is more complex and expensive • If however, simplicity and cost are significant issues, look to produce a common blend (particle size of APIs should be similar), and by understanding of degradation pathways stabilise the blend and compress or encapsulate.

24. Role of Processing in Product Instability • High energy processes (milling, lyophilisation, granulating, drying) can introduce certain amounts of amorphicity into otherwise highly crystalline material. • As has been previously indicated, enhanced levels of amorphicity lead to increased local levels of moisture, and increased chemical reactivity in these areas. • The impact of a roller-compaction process on the water vapour sorption of a sample of aspirin has been reported. Speculated that this was attributed to increased levels of amorphicity (10%) in the sample. • It has also been shown that ball milling causes irregularity, surface faults and imperfections in aspirin crystals. The degree of crystal damage could be directly correlated with the energy of the milling process.

25. Summary and Conclusion • Stress Testing of API • Impact on API Specifications • Pre-Formulation Investigations • Solid State Degradation • Role of Excipients in API Instability • Hydrolysis • Oxidation • Photolysis • Miscellaneous Degradation • Selection of Processing Method • Processing Strategies for Combination Products • Role of Processing in Product Instability