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Table 4.4. Techniques for testing drug-excipient compatibility and utility of data [207, 252]
Technique Measurement Utility of information
DSC Energy is absorbed or released by a sample as it is heated, cooled or held at a constant temperature
Physicochemical compatibility of API and excipient,
polymorph characterisation TGA Weight changes by a sample as it
is heated, cooled or held at a constant temperature
Physicochemical compatibility of API and excipient,
Stoichiometry of solvates and hydrates
Chromatographic
Analysis Chemical interactions of the sample with stationary and mobile phase
Excipient, API and drug product purity; excipient-API compatibility
Micro-calorimetry Adsorption or release of API from
a solution Physicochemical compatibility
of drug and excipients;
solution application X-ray Diffraction Scattering of radiation by solid
material Polymorph characterisation
SEM Magnified appearance of sample Particle size and morphology LC-MS/MS
FTIR
NMR Hot-stage microscopy
Chromatographic separation and fragmentation of molecular species
Absorption frequencies of functional groups
Molecular arrangement
Magnified appearance of sample
Impurities, degradation product identification Characterisation and
quantification of polymorphs, identification of interactions based on functional groups Studying molecular
arrangement of polymorphs, hydrates and solvates
Studying solid state transition and desolvation events
DSC and TGA are techniques in which there is formation of a new peak as a result of an endothermic or exothermic reaction, and/or the disappearance of a peak. These two techniques have the advantage of being rapid analytical approaches [245]. TGA was used for thermal analysis of NVP while DSC and FT-IR where used to evaluate NVP-excipient compatibility in these studies. DSC and FT-IR were chosen as the equipment was readily available and were considered suitable to provide preliminary insight into NVP-excipient compatibility using thermal and non-thermal analytical techniques.
4.4.1 API-Excipient Interactions
Most excipients are pharmacologically inert, however chemical or physical interactions with API are often encountered and may affect the efficacy of a dosage form and/or API. The
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multi-component nature of some excipients and formulations is usually the driving force of many of the interactions observed between an API and the components of a dosage form [253].
4.4.1.1 Mechanism of API-Excipient Interactions 4.4.1.1.1 Physical Interactions
A number of API excipient interactions do not involve any chemical changes in either of the compounds and whilst they are common, such interactions are difficult to detect. Physical interactions are frequently observed and/or used during the manufacturing process but are more often unintended and may cause manufacturing problems. Different physical interactions have been recognised and include the formation of solid dispersions, complexation and adsorption [254].
An example of a physical interaction that has been observed between primary amines and MCC results in the API binding to the MCC and is subsequently not released during dissolution testing and which is of particular importance for low dose drug products [253]. A further example of a physical interaction occurs during interactive mixing during which small particles interact with the surfaces of large carrier particles to ensure that a homogeneous powder blend is produced [253].
4.4.1.1.2 Chemical Interactions
Chemical interactions involve a reaction(s) between an API and an excipient and/or an API and impurities that may be present in the excipients. Chemical interactions are almost always detrimental to the stability and performance of a product as they generally result in the production of degradation products [253].
An example of a typical chemical interaction that often occurs is an interaction between the primary amine functional groups and the glycosidic hydroxyl group of the reducing sugars that precipitates a Maillard reaction to form imine that degrades further to form amidori type compounds and which has been observed with chlorpromazine and dextrose [255].
4.4.1.2 Beneficial API-Excipient Interactions
These interactions result in the formation of a dosage form with desirable characteristics and are usually physical in nature. An example is the simple manufacture of solid dosage forms in
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the presence of Mg stearate which interacts with other excipients resulting in lubrication of powder blends. A further example includes cases where complexing agents such as cyclodextrins are reversibly bound to an API to form complexes that improve the bioavailability of poorly soluble drugs [256].
4.4.1.3 Detrimental API-Excipient Interactions
These interactions result in performance failure of dosage forms. For example, Mg stearate is known to cause reduced tablet strength and impact the dissolution rate of an API from tablets and capsules if it is used at high levels or if powders are subject to prolonged blending and this has been attributed to the hydrophobic nature of Mg stearate [257, 258].
The adsorption of API molecules onto the surface of an excipient(s) may result in an API being sequestered and not released during dissolution of a dosage form which may ultimately result in low bioavailability. An example of such an interaction includes the reduction of antibacterial activity of cetylpiridinium chloride when Mg stearate is used as a lubricant in a formulation. This is due to the adsorption of the cetylpiridinium cation by the stearate anion of the Mg stearate. [257-259].
Colloidal silica catalyses the degradation of nitrazepam in a solid dosage form, possibly due to adsorptive interactions altering the electron density of the labile azo functional group, thereby facilitating hydrolytic attack of the parent molecule [260]. Phenobarbital is known to form an insoluble complex with PEG-400 resulting in decreased dissolution and subsequently absorption of the API [261].
The release of diclofenac sodium from a matrix tablet was inhibited by the polymer chitosan at low pH, most likely due to the formation of an ionic complex between the diclofenac sodium and the ionised cationic chitosan polymer [262].
In a vitamin formulation it was reported that the decomposition of ascorbic acid was increased when silica gel was added to the formulation. This was possibly due to the presence of trace metals such as iron and/or copper that is known to catalyse the decomposition of ascorbic acid in solution [263].
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4.5 EXPERIMENTAL