Impact of QbD approach on nanocrystal formulation

Quality of a substance can be defined as its overall fitness for intended use. Any product designed by formulation scientists is required to be free of contamination and reproducibly deliver the therapeutic efficacy that is promised to the patient on the product label. The quality of pharmaceutical formulations is a function of several critical variables like the nature of the Active pharmaceutical ingredient (API) used, the excipients utilized in the formulation, the concentration of the API and excipient and the process followed for manufacturing the particular formulation. After successful formulation of any pharmaceutical product, its quality can be accessed by conducting several in vitro and in vivo performance tests relevant for that particular formulation.

Quality-by-Design approach refers to predicting and obtaining a certain quality of formulation by controlling the varied parameters relevant for that particular formulation. The approach aids in minimizing the wastage of excipients that is normally encountered while using the trial-and-error  method of formulation development. For successful application of this approach, studying the numerable variables of the formulation and understanding the interaction between the variables of formulation is a must.

In a developing country like India, the healthcare scenario is constantly changing. Ageing population and a panaroma of lifestyle diseases has created an urge for development of new medicines. However the increasing healthcare costs, a rising trend of informed consumers and a higher need to demonstrate economic values has given rise to a pressure to reduce the cost price of medicines. These pressures have driven to Innovation. Nanonization of poorly-soluble API has currently been a topic of wide interest in pharmaceutical industry.  The process comprises of size reduction of a micron-sized API to submicron size with an aim of increasing the dissolution velocity and hence bioavailability of the API. The process comprises of two approaches Top-Down and Bottom-up. Top-Down approach comprises of comminuting the API by techniques like High-speed homogenization, High pressure homogenization and Wet media milling. Bottom-up process of nanonization comprises of obtaining submicron sized API by micro-precipitation, chemical synthesis and complexation. One of the critical step of Nanonization is obtaining a nanosuspension. Out of all the described techniques, Wet media milling technique of nanocrystal formulation has been the most widely explored technique because of its industrial feasibility and ease of application.

A nanosuspension comprises of an aqueous suspension of submicron sized drug particles stabilized by stabilizers and surfactants. The nanosuspension can then be transformed into suitable solid oral dosage forms as per the route of administration and targeted health disorder. Formulation of an optimized nanosuspension can be achieved by taking into consideration several parameters like API size, nature of the API, stabilizer suitability etc. A critical attribute of nanocrystal formulation is prevention of Agglomerate formation that is mainly triggered by Ostwald ripening (tendency of particles less than 0.5 microns to dissolve and recrystallize on the larger particles thus leading to instability).

Application of Quality-by-Design approach to Nanocrystal formation comprises of use of statistical experimental designs to study the interaction between varied nanocrystal formulation parameters. Factorial designs have been utilized in experiments to simultaneously determine the effect of different variables on the dependent variable of the formulation. Attributes like Concentration of drug and stabilizer are considered as the Independent variables and the resultant particle size, polydispersity index and percent of drug released after a specific duration from the formulation are considered as the Response or Dependent variables. The 32 Factorial design has been utilized for nanocrystal formulation using techniques like Antisolvent addition method of Nanoprecipitation. This factorial design aids to study the impact of critical parameters like the concentration of the diffusing drug and the amount of stabilizer required for nanosuspension formulation. Response surface methodology is another technique used frequently in nanonization. Factorial design is employed via utilization of principle of  Design-of-Experiments. The most optimized nanoformulation containing nanocrystal can be obtained by planning a Design-of-Experiments that includes use of several  types of Experimental designs involving the parameters of relevance in nanosuspension formulation.

Once the experimental design is generated, polynomial equations are created and response over the domain of interest are generated. Polynomial equations aid to correlate the independent variable with the response generated by it. The influence of the independent variables on the selected responses is studied by Contour plots and surface response plots.

Design Expert softwares are used to generate computations of Response Surface Methodology, 2D contour plots and 3D graphs. The significance of the various generated parameters on the variables can be studied by using statistical techniques like Two Way Analysis of Variance(ANOVA).  Using all the mathematical modeling and the data generated, a desirability function is generated for the response of interest. A Desirability function aids to combine all the responses into one variable which aids to predict the optimum levels for the independent variables. A desirability value of 0 indicates unacceptable value (unsuitability) of responses and a desirability value of 1 indicates the most desirable value for responses.

Thus by using the Quality-By-Design Approach for nanocrystal formulation, formulation parameters are optimized to find levels of variables that affect the critical response. This aids to obtain the levels of variables from which a nanosuspension product with desirable characteristics can be obtained. For nanocrystal formulation, where the stability of the formulation is a critical attribute contributed to the type and concentration of stabilizer used, the Quality-By-Design approach can aid to predict the exact type and  concentration of stabilizer that can give  a stable nanosuspension thus decreasing the chances of failure of formulation. In addition, as the critical parameters for a successful nanosuspension can be predicted, more efforts can be put on the other related aspects of pharmaceutical manufacturing like packaging and storage thus making the pharmaceutical production of nanocrystal dosage form a less formidable  task for  formulation scientists.