Formulation Development Optimization

Various experimental designs have been explored by Vojnovic et al. to optimize wet-granulation process variables. Some of these examples are described below. 

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Product bioavailability is mentioned, especially where it is low. Where there are differences between the formulations tested for bioavailability during the development process and the formulation to be marketed, there is considerable discussion of the data provided on the bioequivalence of the different products and/or formulations. This is particularly so where, for example, early clinical studies were undertaken with capsules but the marketed dosage form is to be a tablet. Bioequivalence data and pharmacokinetic data (e.g., in crossover studies) and comparative dissolution studies are usually reported. This is particularly significant where the different strengths of the final products are not achieved by using different quantities of the same granulate formulation. Process optimization may also be addressed in such cases. 

Publications on optimal design of tree networks are further divided into single-branch trees or pipelines (C6, F4, L3, L6, S8) and many-branch trees (B7, C7, F4, Kl, K2, M3, M9, Nl, R5, W10, Y1, Zl). For our purposes, since the pipeline problems can always be solved using the optimization methods developed for the many-branch tree networks, we need to dwell no further on this special case. On the other hand, it is important to note that the form of the objective function could influence the applicability of a given optimization method. For the sake of concreteness, problem formulations and optimization techniques will be discussed in the context of applications. 

Table 6 shows the usefulness of shear cell data in formulation development. Variations in relative humidity can profoundly influence flow this is a valuable piece of information for formulation development. Shear cell methodology thus provides useful data for optimizing the flow of formulations as well. 

Preclinical animal studies are usually performed with simple formulations which are appropriate for the route investigated in the (nonhuman) species involved. While similar simple formulations or approaches (such as capsules) are also employed for first-in-man studies, as development proceeds, efforts are made to develop formulations which optimize bioavailability. This may lead to effects not seen in earlier animal (or, indeed, human) studies, a factor that should be kept in mind in both study design and interpretation. 

Key operating parameters that may change (or be optimized) throughout a product s development and approval cycle are dissolution sampling time points and dissolution limits or specifications by which the dissolution results should be evaluated. The results generated from the dissolution test need to be evaluated and interpreted based on the intended purpose of the test. If the test is used for batch-to-batch control, the results should be evaluated in regard to the established limits or specification value. If the test is being utilized as a characterization test (i.e., biopharmaceutical evaluations, formulation development studies, etc.) the results are usually evaluated by profile comparisons. 

An MEKC method for the determination of ibuprofen, codeine phosphate hemihydrate, their nine potential degradation products, and impurities in a commercial tablet formulation was developed, optimized, and fully validated according to ICH guidelines and submitted to the regulatory authorities. The optimized system containing ACN as organic modifier allowed baseline separation of ibuprofen, codeine, and nine related substances within 12 min. 

The key objective of our efforts has been to develop a vaginal formulation that optimizes spermicidal and antiviral activity while enhancing spreading and true bioadhesiveness. Utilization of strict design principles for an excipient delivery vehicle, which included substantivity to vaginal mucosa, saline compatibility, compatibility with a wide range of spermicidal and antiviral compounds, low irritation potential, sperm impedance, system stability, and efficacy after stressed storage conditions, resulted in the development of DCE s [11,12,13]. Based on the results from in vitro studies, the DCE vehicle was selected for clinical development. 

When these methods are unsuitable, nonlinear methods may be applied. The function local minima and overall computational efficiency. The function (u) is often expensive to compute, so maximum advantage must accrue from each evaluation of it. To this end, numerous methods have been developed. Optimization is a field of ongoing research. No one single method is best for all types of problem. Where (u) is a sum of squares, as we have expressed it, and where derivatives dQ>/dvl are available, the method of Marquardt (1963) and its variants are perhaps best. Other methods may be desirable where constraints are to be applied to the vt, or where (u) cannot be formulated as a sum of... 

Formulation Development. The formulation of the new drug product will be designed in conjunction with medical and marketing input. Excipients to be used will be tested for chemical and physical compatibility with the drug substance. The preliminary formulation design will be optimized at this stage. 

The rational development of a drug delivery system can be timely and costly. Formulation development and optimization requires a step-wise approach by Lrst screening and evaluating various formulationsin vitro before one initiates formulations/dosage forms tesfringvo. 

Today, there is more emphasis on quality of excipients. For example, some inherent quality variability may occur in the natural products magnesium stearate and sodium starch glycolate. What is the impact of the variability of these excipients on product quality attributes Also, excipient viscosity, molecular weight, and particle size relative to API particle size could be critical factors to some formulations. An optimal dissolution method can only be developed on the basis of knowledge of the dmg product. 

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