Drug release profiles

The process of formulation for any of the above is generically the same, beginning with some form of product specification and ending with one or more formulations that meet the requirements. Correct choice of additives or excipients is paramount in the provision of efficacy, stability, and safety. For instance, the excipients may be chemically or physically incompatible with the drug or they may exhibit batchwise variability to such an extent that at the extremes of their specification they may cause failure in achieving the desired drug release profile. In addition, some excipients, especially those that are hydroscopic, may be contraindicated if the formulation is to be manufactured in tropical countries. Flence formulators must work in a design space that is multidimensional in nature and virtually impossible to conceptualize. 

Iyer et al. [50] investigated the effects of roto-granulation on the performance of hydroxypropyl methylcellulose (HPMC), gelatin, and poly(-vinylpyrrolidone) (Povidone, PVP). In this process, all three binders produced similar results. However, HPMC was preferred due to prolonged drug release profiles, smaller particle size, and better content uniformity. 

In order to produce an adequate tablet formulation, certain requirements, such as sufficient mechanical strength and desired drug release profile, must be met. At times this may be a difficult task for the formulator to achieve, due to poor flow and compactibility characteristics of the powdered drug. This is of particular importance when one only has a small amount of active material to work with and cannot afford to make use of trial-and-error methods. The study of the physics of tablet compaction through the use of instrumented tableting machines (ITMs) enables the formulator to systematically evaluate his formula and make any necessary changes. 

Fig. 8.12 Comparison of drug-release profiles recorded in simulated gastric medium (pH =2) for (a) ibuprofen-AMP nanocomposite and (b) control sample (ibuprofen-talc suspension).

The erosion of copolymers requires the hydrolytic cleavage of three bond types the A A bond, the A-B bond, and the B-B bond. If the degradation rates of these three bonds are unequal, as is likely the case, then the erosion will be inhomogeneous. And, if drugs are inhomogene-ously distributed in the polymer matrix, the drug release profile will not follow overall device erosion (Shen et al., 2002). Therefore, it is necessary to accurately describe the microstructure of microphase-separated systems. 

The simplest model for pure erosion control with kinetics dominated by a single rate constant and uniformly distributed drugs was described by Hopfenberg (1976). This model says nothing about the various physical phenomena that contribute to erosion, and therefore fails to describe drug release profiles from many poly anhydride systems. Below we classify some of the models that can be found in the literature. 

The past two decades have produced a revival of interest in the synthesis of polyanhydrides for biomedical applications. These materials offer a unique combination of properties that includes hydrolytically labile backbone, hydrophobic bulk, and very flexible chemistry that can be combined with other functional groups to develop polymers with novel physical and chemical properties. This combination of properties leads to erosion kinetics that is primarily surface eroding and offers the potential to stabilize macromolecular drugs and extend release profiles from days to years. The microstructural characteristics and inhomogeneities of multi-component systems offer an additional dimension of drug release kinetics that can be exploited to tailor drug release profiles. 

FIGURE 6.41 Comparison of drug release profiles obtained by HPLC and by /iPLC, as reported by Liu... 

This chapter provides an introduction to the pharmaceutical sector, and the business of developing new active pharmaceutical ingredients (API). Crystallization is the preferred method of isolating commercial API products because it offers a highly efficient means of purification. The crystallization process is also where the physical properties of the drug substance are defined. These properties can have a significant impact on the formulated product and process, and eventually on the drug release profile in the patient. 

One challenge that remains in biopharmaceutics research is that of correlating in vitro drug-release profiles with the in vivo pharmacokinetic data. TVIVC has been defined by the... 

Joergensen K, Jacobsen L. Factorial design used for ruggedness testing of flow through cell dissolution method by means of Weibull transformed drug release profiles. Inti J Pharm 1992 88 23-29. 

Figure 2 Simulated in vitro drug-release profiles (panels a and b) and resultant plasma concentration—time profiles for a drug with a 1—hr half-life (panel c) and a 6—hr half-life (panel d).

Table 1 Comparison of Predicted Pharmacokinetic Parameters for Two Different Drugs with Identical In Vitro Drug Release Profiles, But Different Drug Disposition Characteristics (ty2 = 1 or 6 hr)...

Table 2 Fitted Weibull Parameters for the Three In Vitro Drug-Release Profiles Shown in Figure 3...

In order to obtain an in vitro-in vivo relationship two sets of data are needed. The first set is the in vivo data, usually entire blood/plasma concentration profiles or a pharmacokinetic metric derived from plasma concentration profile (e.g., cmax, tmax, AUC, % absorbed). The second data set is the in vitro data (e.g., drug release using an appropriate dissolution test). A mathematical model describing the relationship between these data sets is then developed. Fairly obvious, the in vivo data are fixed. However, the in vitro drug-release profile is often adjusted by changing the dissolution testing conditions to determine which match the computed in vivo-release profiles the best, i.e., results in the highest correlation coefficient. 

For an extended-release dosage form, at least three test time points are chosen to characterize the in vitro drug-release profile for the routine batch-to-batch quality control for approved products. Additional sampling times may be required for formulation development studies, biopharmaceutical evaluations, and drug approval purposes. An early time... 

Prior to formulating a drug substance into a dosage form, the desired product type must be detemined for planning the product formulation activities. Then, various initial formulations are developed and then evaluated for selected parameters, such as drug-release profile, bioavailability, clinical effectiveness, and for any scale-up problems. The best formulation is selected and becomes the master formula. Each batch of the product subsequently prepared must meet the specifications established in this master formula. 

The functional characteristics (in terms of drug release) for the pellets coated in this particular study are shown in Figure 16. Statistical comparison of these data (using the /2 factor) confirms that these drug release profiles are essentially equivalent, although the best comparison, as is evident... 

Drug release profiles from the tablets in various dissolution media are shown in Fig. 2. In all cases the release rates decreased initially from the control (distilled water) as electrolyte concentration increased, until a minimum release rate was obtained. As the electrolyte concentration further increased the release rates similarly increased until a burst release occurred. These initial decreases in release rates were probably coincident with a decrease in polymer solubility, in that as the ionic strength of the dissolution medium is increased the cloud point is lowered towards 37°C. It may be seen from Table 5 that minimum release rates occurred when the cloud point was 37°C. At this point the pore tortuosity within the matrix structure should also be at a maximum. It is unlikely to be an increase in viscosity that retards release rates since Ford et al. [1] showed that viscosity has little effect on release rates. Any reduction in hydration, such as that by increasing the concentration of solute in the dissolution media or increasing the temperature of the dissolution media, will start to prevent gelation and therefore the tablet will cease to act as a sustained release matrix. 

The effect of basket rotation rate and pH on the release profile of ketoprofen from the KET-R tablet is presented in Fig. 2. The release rate of ketoprofen from the system increased with increasing basket rotation rate and changed from 11%/h at 50 rev/min to 16%/h at 150 rev/min, but the profile remained linear up to 80% drug content. Moreover, the drug release profile at pH 6. 8 (y=0.189x-1.091, r= 0.99) was very similar to that at pH 1.2 and thus the ketoprofen released... 

The present study was undertaken to investigate the effect of physicochemical properties of wall-forming materials on the drug release kinetics and bioavailability of microcapsules and micromatrices. The effect of a coacervation-inducing agent on the drug release profile was also studied. 

Table 2—In vitro drug release profile of microcapsules and micromatrices...

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