Drug substance solutions

A 2-Dimensional experiment is done to determine if there are any TLC artifacts, or what are known as TLC procedure-related effects. In this study, a spot of drug substance at nominal concentration, usually 25 mg/ml, is placed on the HPTLC plate by making one spot by overlaying 3 applications of 5 pi each. This yields one tight spot that contains 15 pi of drug substance solution, rather than a large spot that pools by performing one application. The HPTLC plate is then developed in the usual manner and dried. The plate is then rotated 90° and a second... 

One major potential problem with the use of additives in primary containers is the possibility of their migration into the drug substance/solution stored therein. To exclude this potential risk, the use of colored plastic sleeves, placed over the primary containers, is recommended. Using this approach, the primary packaging remains unchanged and the photo protective additives do not come in direct... 

The next example, compound 4, is a precipitate formed during a drug substance solution solubility experiment. This material exhibited physical properties that were not similar to the drug substance. Thermal analysis of this material generated the data presented in Figure 7.32, which shows the material exhibiting endothermic transitions at 68.1 and 267.7°C, and an exothermic transition at 220.5°C, and a 3.9% weight loss measured at 150°C was observed in the TGA curve. This material... 

The necessary reference samples are produced by preparing a stock solution of the pure drug substance and diluting it to the required concentrations. On the average, 12 minutes are needed per reference. 

At the limiting concentration the enhancer will bind all available water in hydration shells, leaving none to participate in the solution of the drug substance. 

The testing of impnrities in active pharmacentical ingredients has become an important initiative on the part of both federal and private organizations. Franolic and coworkers [113] describe the utilization of PLC (stationary phase — silica gel and mobile phase — dichloromethane-acetonitrile-acetone (4 1 1, v/v)) for the isolation and characterization of impurities in hydrochlorothiazide (diuretic drug). This drug is utilized individually or in combination with other dmgs for the treatment of hypertension. The unknown impurity band was scraped off the plate and extracted in acetonitrile. The solution was filtered and used for LC/MS and NMR analysis. The proposed procedure enabled the identification of a new, previonsly nnknown impurity. It was characterized as a 2 1 hydrochlorothiazide-formaldehyde adduct of the parent drug substance. 

Bioavailability depends not only on having the drug in solution, but also on the drug s permeability. A jejunal permeability of at least 2-4 x 10 4cm/s, measured in human subjects by intubation, is considered high [97]. For many drugs and other substances, this permeability corresponds to a fraction absorbed of 90% or better. Amidon et al. [97] thus proposed a Biopharmaceutics Classification System (BCS) for drugs based on the above definitions of these two parameters. Table 3 defines the BCS and includes some drugs representative of each class. 

One approach to the study of solubility is to evaluate the time dependence of the solubilization process, such as is conducted in the dissolution testing of dosage forms [70], In this work, the amount of drug substance that becomes dissolved per unit time under standard conditions is followed. Within the accepted model for pharmaceutical dissolution, the rate-limiting step is the transport of solute away from the interfacial layer at the dissolving solid into the bulk solution. To measure the intrinsic dissolution rate of a drug, the compound is normally compressed into a special die to a condition of zero porosity. The system is immersed into the solvent reservoir, and the concentration monitored as a function of time. Use of this procedure yields a dissolution rate parameter that is intrinsic to the compound under study and that is considered an important parameter in the preformulation process. A critical evaluation of the intrinsic dissolution methodology and interpretation is available [71]. 

The other main approach to solubility is to measure the concentration of the drug substance after an equilibrium has been reached with the solvent in question. This work is also conducted very early during the development process, normally at the stage of preformulation characterization [7]. A full discussion of the various aspects of solution theory is beyond the scope of the present chapter, but it is available [68]. Only a few salient points will be addressed in the following paragraphs. 

Nuclear magnetic resonance (NMR) spectroscopy in pharmaceutical research has been used primarily in a classical, organic chemistry framework. Typical studies have included (1) the structure elucidation of compounds [1,2], (2) investigating chirality of drug substances [3,4], (3) the determination of cellular metabolism [5,6], and (4) protein studies [7-9], to name but a few. From the development perspective, NMR is traditionally used again for structure elucidation, but also for analytical applications [10]. In each case, solution-phase NMR has been utilized. It seems ironic that although —90% of the pharmaceutical products on the market exist in the solid form, solid state NMR is in its infancy as applied to pharmaceutical problem solving and methods development. 

Investigations for the occurrence of polymorphism have been undertaken by ir spectroscopy, differential scanning calorimetry and x-ray powder diffraction (Guinier-de Wolff). No polymorphism has been observed so far. An amorphous form may be prepared artificially by rapid evaporation of a methanolic solution of the drug substance. 

Samples are usually prepared by weighing a 25 mg sample of drug substance and placing it into an appropriate vial. One millileter of organic solvent, such as methanol, is then added to the vial. The sample is sonicated for 1-2 min, until solution is clear, and now ready to be applied to HPTLC plates. 

When a TLC method is validated, two of the tests that are done are (1) stability on plate and (2) stability in solution of the drug substance to determine how quickly a sample must be applied to the HPTLC plate and developed before degradation occurs, if it occurs at all. For example, five vials are prepared by placing 25 mg of drug substance in each vial, and labeling them as time 0,1,2, 3, and 4 h. The experiment begins... 

The five vials on the bench top are also then applied to a fresh HPTLC plate to examine any degradation of the drug substance in solution. In this case, the plates looked very similar, indicating similar degradation in solution within 1 hour also. 

Solutions to practical problems rarely depend upon a single technique or a single approach. The following example of an impurity identification in a pharmaceutical product illustrates the key role that LC-MS can play in such an investigation, but also illustrates the limitations of the technique. The identification of this impurity has been published elsewhere in complete detail [75]. The problem and solution is summarized here. The impurity, designated as H3, was observed at 0.15% in a bulk lot of the drug substance in the structure below. The impurity required identification before the bulk lot could be released for use in further studies. 

The sodium chloride equivalent method is the most frequently used method in the calculation of the amount of sodium chloride needed to prepare isotonic drug solutions. The sodium chloride equivalent of any drug substance, as discussed earlier, is the amount (in grams) of sodium chloride that is osmoti-cally equivalent to 1 g of the drug. The sodium chloride equivalents for selected compounds are listed in Table 8.2. 

The volumes of isotonic solutions prepared in milliliters from a gram of selected drug substances are listed in Table 8.3. 

TABLE 8.3. Volume of Isotonic Solutions Prepared (in Milliliters) from 1 g of Drug Substance. 

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