Acetate buffer formulations

To test the robustness of the formulation to variations in gastric pH, dissolution results should be obtained in both the pH 2 medium described in Table 3 and a model which reflects the conditions in the hypochlohydric stomach. A good choice would be acetate buffer adjusted to pH 5 and having a very low buffer capacity, since hypochlorhydria is generated by a reduction in HCl secretion rather than the addition of buffer species. 

Results for the release of the drug whose solubility is depicted in Figure 6 from two differently constituted formulations in SGFsp at pH 1.2 and an acetate buffer at pH 5 are shown in Figure 7. The discrimination with respect to robustness of release using the higher pH medium is clearly... 

The extract was then diluted with 0.5 mL with 0.2 M sodium acetate buffer, pH 4.7 and analyzed by HPLC. Chromatographic conditions were the same as for the determination of benzidine in hair dye formulations. For the particular lot of diarylide yellow studied 46 Ug/kg of DCB was found. In an attempt to confirm the identity of the chromatographic peak, its response as well as the response for the authentic DCB standard was determined at several different electrode potentials. These data, shown in Figure 7, illustrate the ability of HPLC/EC to yield qualitative as well as quantitative information for unknown components. 

A high-performance, liquid chromatography (h.p.l.c.) assay (reversed phase, C lg column, methanol - water- acetate buffer) for isosorbide dinitrate along with the two mononitrates in pharmaceutical formulations has been described.45 A similar method can be found in Ref. 44. 

CR845 is a novel peripherally restricted, all-d-amino acid tetrapeptide kappa opioid selective agonist under development for the treatment of acute and chronic pain. It belongs to a novel class of opioid ligands which has a reduced ability to cross the blood-brain barrier and therefore acts without inducing central side effects [1]. It is currently available as an intravenous formulation in a sterile isotonic 0.04 M acetate buffer of pH 4.5 composed of acetic acid, sodium acetate trihydrate, sodium chloride, and water, with addition of hydrochloric acid for pH adjustments. 

Since the principal hazard of contamination of acrolein is base-catalyzed polymerization, a "buffer" solution to shortstop such a polymerization is often employed for emergency addition to a reacting tank. A typical composition of this solution is 78% acetic acid, 15% water, and 7% hydroquinone. The acetic acid is the primary active ingredient. Water is added to depress the freezing point and to increase the solubiUty of hydroquinone. Hydroquinone (HQ) prevents free-radical polymerization. Such polymerization is not expected to be a safety hazard, but there is no reason to exclude HQ from the formulation. Sodium acetate may be included as well to stop polymerization by very strong acids. There is, however, a temperature rise when it is added to acrolein due to catalysis of the acetic acid-acrolein addition reaction. 

Figure 12.1 Clearance of small-molecule impurities from process buffers in a formulated protein product. Trace A the NMR spectrum of a control sample containing a mixture of three components (succinate, tetraethylammonium, and tetramethylammonium) in the final formulation buffer (sodium acetate). These three components were used in the recovery process for a biopharmaceutical product. Traces B and D the proton NMR spectra of the formulated protein product. No TEA or TMA were detected, but a small amount of succinate was observed in this sample. Traces C and E the proton NMR spectra of a formulated protein product spiked with 10 jag/ml of succinate, TEA, and TMA. Traces D and E were recorded with CPMG spin-echo method to reduce the protein signals. The reduction of NMR signals from the protein allows for better observation of the small-molecule signals.

The pH dependence of dorzolamide solubility was also determined between pH 4.0 and 7.0, using acetate, citrate, and phosphate buffer solutions to set the desired pH. These data are collected in Table 2 (also plotted in Figure 4), and show a maximum solubility of approximately 40 mg/mL at pH 5.6. The equilibrium solubility decreases to approximately 13 mg/mL at pH 6 and 4 mg/mL at pH 7.0. These data indicate that in order to have a stable 2% solution for an ophthalmic formulation, the solution pH should be maintained below 5.8. At pH values exceeding 5.8, precipitation of the free base could occur. 

The reactions in Table 13.8 show that carbon dioxide is a common product in many neutralization reactions. This is clearly displayed when a drop of vinegar (acetic acid) is added to baking soda (sodium bicarbonate). Some aspirin includes an antacid in their formulation to neutralize some of the acidity imparted by the aspirin (acetylsalicylic acid). These are commonly referred to as buffered aspirins. 

Buffers for lyophilized formulations need additional consideration. Some buffers like sodium phosphate can crystallize out of the protein amorphous phase during freezing resulting in rather large shifts in pH. Other common buffers such as acetate and imidazole should be avoided since they may sublime or evaporate during the lyophilization process, thereby shifting the pH of formulation during lyophilization or after reconstitution. 

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