Stress testing combination drugs

Stability testing of drugs is its own subspecialty. In brief, it is the research pharmacist s duty to stress test drugs in storage using factorial combinations of... 

As discussed in Sect. 18.3, several models are available and can be applied with limited amounts of experimental data in combination with calculated molecular descriptors. These models are extremely valuable at the early stage of development of the API. A quick decision can be made regarding if ASD is an applicable approach for the candidate. Once this question is answered, the selection of an appropriate polymer comes in as the next step. If other additives are needed, for example, a surfactant to improve the manufacturability or to enhance the pharmacokinetic (PK) performance, the implication on system stability has to be assessed. The different formulations developed can be rank ordered based on their stability under severe temperature and humidity conditions. When the composition of the ASD is finalized, a more systematic stress test is used to understand the recrystallization risk. Though the changes in physicochemical properties by and large appear in a nonlinear fashion, the stress tests normally are sufficient to assess the risks, thus providing the formulation scientists confidence to estimate the stability of the drug product. 

Fig. 5.4 Phase maps recorded from fracture surfaces of a 50 % drug loading (w/w) test compound A—PVP VA 64 combination by tapping-mode AFM. The maps indicate the surface homogeneity of the mixture on the nanometer scale. Left, homogeneous surface before stress treatment. Right, heterogeneous surface after sample exposure to stress conditions (40 °C/75 % RH for 2 h) indicating phase separation. The scale bars correspond to a length of 1 p.m...

This process should be sufficient to exclude excipients that cause chemical degradation, A drop in potency (compared to the initial extraction of the T=0 sample) combined with an increase in degradation products will be a clear indication that a chemical degradation is occurring with that given excipient. The question of what happens to the solid-state properties of the drug component still remains. The samples which were stored under accelerated conditions for the chemical compatibility study can be tested by a solid-state test such as X-ray powder diffraction. This will demonstrate that the crystal form of the API will remain unchanged under these stressed conditions, and in contact with the excipient under consideration. 

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