Presence of Excipients

Lyoprotectants can affect enzyme stability in both stages of lyophilization the freezing and the drying stages. In the freezing stage of lyophilization, ice crystals form and have been shown to be a cause of enzyme denaturation. Studies have shown that when added as a lyoprotectant, the amorphous polyol mannitol stabi- 

---

With the exception of antimicrobial preservatives and antioxidants (see below) and coloring matter (for which an identity test should be available), it is not normally necessary to test for the presence of excipients in finished products. 

Besada et al. [13] described spectrophotometric methods for determination of penicillamine in pure and dosage forms. Penicillamine was measured spectrophoto-metrically in 0.1 M HC1 (at 195 nm) or in 0.1 M NaOH (at 238 nm). Both methods gave recoveries of 100% with good precision. For determination of the drug in tablets, in the presence of excipients, ground samples were extracted with each of these solvents and the difference in absorbance at 238 nm between the two solutions were measured. The recovery of the drug from commercial tablets was 99.8%, with a coefficient of variation of 0.38%. The three methods were suitable for 4—130 ppm of the drug. 

We now turn briefly to the problem of peptide stability in the solid state [8] [88], First, we note that most - if not all - reactions discussed in the previous and subsequent sections can also occur in the solid state, although the kinetics and mechanisms of the reactions can be quite different from those observed in solution. Moisture content, the presence of excipients that act as catalysts, and surface phenomena are all factors whose roles are all-but-im-possible to predict. As a result, each formulation poses a new challenge to pharmaceutical scientists. As a rule, solution data cannot be used to predict the shelf-life of solid formulations, and extrapolating from one solid formulation to another can be misleading. 

The aggregate-specific ELISAs could be used to monitor the aggregate-inducing processes during IFN-a formulation and storage in an early phase and the development of aggregate-free IFN-a formulations. The ELISAs were highly sensitive, needed low protein concentrations, worked in the presence of excipients, and required no pretreatment.6... 

Only products with chromatograms suitable for quantification were presented. Owing to the presence of excipients, NPNl and NPN2 could not be quantified using HPLC-DAD. These products were omitted in subsequent statistical comparisons and correlations. 

Compression properties are important in determining the ability of the compound to form tablets with or without the presence of excipients. 

Intuitively such delivery systems or excipients would best achieve this objective if they were to be composed of natural products or their modifications an overwhelming presence of excipients under this category (discussed in Ref. 1) provides credence to this observation. The substitution of natural products comprising complex proteins, antibodies, chimera, or toxins in lieu of stand-alone simple inorganic molecules as excipients for parenteral drug delivery represents a paradigm shift in the introduction of emerging excipients in the therapeutic armamentarium. 

Once good physical stability of an emulsion is insured, its commercialization mandates chemical stability of the incorporated drug and other essential components for at least 18 months. Key factors that affect the chemical stability of pharmaceutical emulsions include drug stability in oil, drug stability in aqueous media, drug concentration in oil and emulsion, phase volume ratio, droplet size, presence of excipients, and presence of air and/or peroxide radicals. As mentioned earlier, choice of appropriate antioxidant is important. 

In the process of stressing API in the presence of excipients, one should take into account the potential for physical change of the API to occur in the formulation mixtures being evaluated. Depending on the stage of development and the depth of excipient compatibility studies, physical form assessment may be cursory or more extensive, but should be considered at some level. 

Mroso P, Li Wan Po A, Irwin W. Solid-state stability of aspirin in the presence of excipients kinetic interpretation modeling and prediction. J Pharm Sci 1982 71(10) 1096—1101. 

Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption. 

The factors influencing the release of drugs from hydrophilic matrices include viscosity of the polymer, ratio of the polymer to drug, mixtures of polymers, compression pressure, thickness of the tablet, particle size, pH of the matrix, entrapped air in the tablet, solubility of the drug, the presence of excipients or additives, and the mode of incorporation of these substances. 

Many times, depending upon the active-to-excipient ratio, the solubility of active in presence of excipients in certain solvents will be different. When an API is mixed with excipients, its solubility is usually lower when compared to its solubility in the same solvent by itself. 

The results from these two experiments (kinetic and thermodynamic) will show whether the regular extraction procedure is complete or not. Most hkely, for modified-release drug products, time is essential (higher recovery over time, but watch out for solution stabihty ). The change in volume will have an impact if the solubihty of an API is on the border of the solubility limit in that particular sample preparation solvent (in the presence of excipients). If the latter is the case, then the procedure should be modified to extract with higher volume of sample preparation solvent and/or change the pH or composition of the solvent. 

Several investigations on the photostability of certified dyes have been conducted. As with drugs, the photostability of the different colorants depends on test conditions employed (pH, temperature, and radiation intensity) (24) and the presence of excipients in the formulation (25-27). Colorants absorb both UV and VIS radiation. The UV radiation contributes significantly to fading. Hence, UV absorbers (28) and sunscreen agents (29-31) can be used to increase their colorfastness. It is interesting to note that lakes are similarly (32) or even less photostable (33) than the... 

A particular drug or dosage form may have features that rely on the presence of excipients for stabilization, delivery, or other performance parameters. Alternatively, the excipient may need to have additional features to render it suitable for the product in question... 

The presence of excipients in a formulation can influence product stability. The conceptually appealing strategy of including a moisture scavenger in a formulation is based on this. In glucose-containing systems, it was demonstrated that liquid and solid... 

Altimaras, J. Nieto-Hernandez, T. Buitrago, F. Presence of excipients in pharmaceutical products in three sources of therapeutic information. Aten. Primaris. 1996, 18 (4), 190-193. 

Due to the very low natural abundance (0.37%) and receptivity (0.066 relative to of the N nucleus, nitrogen-detected experiments often require N-labeled compoimds to obtain good spectra in reasonable amoimts of time, especially if low LODs are needed in the presence of excipients. N SSNMR was used in a study by D Souza et al. to investigate a reaction occurring in a lyophilized peptide/polymer formulation. In this study, N-labeled valine was formulated in a PVP matrix and stored at 70° C for 7 days, with N SSNMR spectra acquired at various intervals. The authors observed at least three nitrogen populations at day 0, two of which disappeared over time, indicating that non-covalent interactions between the peptide and the polymer matrix occurs before the reaction to form an amide bond. 

Table 1 Microcalorimetric kinetic stability studies of degradation of BPO in the presence of excipients in water at 313 K...

When TLC is used to track a specified impurity in the drug substance, it is likely to be applied to the subsequent drug product method. A plate must be prepared to show that required levels of LOD and LOQ can be achieved for the specified impurity in the presence of excipients. This is known as a spiking experiment. The specified impurity is prepared and spiked into the vial of the drug product at different levels, then applied to the TLC plate to ensure it can be extracted to meet the requirement of LOD and LOQ. If no specified impurities are being tracked by TLC, this validation test can be excluded. 

These cells are also helpful at the formulation stages. Very little is known about the effect of excipients on intestinal permeability therefore, it is advantageous to measure the permeation of the active ingredients in the presence of excipients,20 as revealed in recent studies.21... 

The powder s flow properties are also important because they control the physical processes that are used to manipulate the material. Carrs s index, which is a measure of powder bulk density and angle of repose, provides information on flow properties, which are important when production utilises high-speed tableting machines. Compression properties are important in determining the ability of the compound to form tablets wdth or without the presence of excipients. 

Figure 6.7. An example of impurities testing using gradient HPLC of a pharmaceutical product stored under accelerated stability conditions, noting the presence of excipient, preservative (butylated hydroxytoluene, BHT), impurities (Imp), and degradants (DG). HPLC conditions column Waters XTerra MS18, 150 x 3mm i.d., 3pm mobile phase (A) 16mM ammonium bicarbonate, pH 9.1 (B) acetonitrile gradient 3% B to 45% B in 25min flow rate 0.8mL/min at 50°C detection 280nm. Additional information can be obtained from reference 22.

---