Excipient measurement

Table 3 Glass transition temperatures, (Tg), of selected excipients measured by differential scanning calorimetry s...

For a change in formulation such as excipients, measured values (except when there are no effects on the standards and test methods), stability test (in cases that the stability after the change is not worse than before, a relative comparative test) and bioequivalence tests are required. 

T. Otsuka, S. Yoshioka, Y. Aso, and S. Kojima, Water mobility in aqueous solutions of macromoleular pharmaceutical excipients measured by oxygen- 17 nuclear magnetic resonance, Chem. Pharm. Bull. 43, 1221-1223 (1995). 

In an extension of this work, pellets of a blend of PCL and hy-droxypropylcellulose containing fluridone were prepared by grinding, blending, and then melt-spinning the mixture with a Berstorff twin screw extruder (78). The extruded rod was subsequently water-quenched and pelletized. Pellets were also prepared by coating bundles of extruded rods with the water-soluble excipients PEG 3350 and PEG 600 (95 5). In vitro release rate measurements were conducted in the simulant medium of 50% aqueous ethanol or hardened water. 

The intrinsic dissolution rate is usually evaluated by using a rotated disk method (Fig. 7). The pure powdered solute is compressed in a die under high pressure, in the absence of any excipients. The resulting nondisintegrating disk is then transferred to a dissolution cell which has sufficient volume to maintain sink conditions. The die is rotated at a certain speed, and the rate of drug dissolution is then measured. 

Selective differential UV spectrophotometric method was presented for the determination of niclosamide in bulk and in its pharmaceuticals [43]. The method was based on measuring niclosamide in alkaline solutions against their neutral ethanolic solutions as blanks. The proposed method was sensitive, highly specific, and advantageous over the conventional UV assays, since the interference of the excipients, impurities, degradation products, or other accompanying drugs was nullified. 

Niclosamide and its dosage forms were spectrophotometrically estimated by reaction with aqueous 4-aminophenazone in the presence of ammonia and measurement of absorbance of the resulting oxidative coupling product at 520 nm [50], Beer s law was obeyed in the concentration range 1.25-10.0 pg/mL the relative standard deviation was 1.51% and the recovery 98.9 99.6%. Dosage form excipients did not interfere. 

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. 

Measurements of particle porosity are a valuable supplement to studies of specific surface area, and such data are particularly useful in the evaluation of materials used in direct compression processes. For example, both micromeritic properties were measured for several different types of cellulosic-type excipients [53]. Surface areas by the B.E.T. method were used to evaluate all types of pore structures, while the method of mercury intrusion porosimetry used could not detect pores smaller than 10 nm. The data permitted a ready differentiation between the intraparticle pore structure of microcrystalline and agglomerated cellulose powders. 

Surface area and moisture uptake have been related to the disintegration properties of excipients such as crosspovidone, starch, and alginic acid [17]. The surface areas of the three materials were measured, and a linear correlation was found between the maximum moisture sorption and specific surface area for the three disintegrants. The greater the surface area of the material, the more numerous were the sites for capillary attraction of water to its surface. It was postulated that the capillary action appears to be responsible for the disintegration properties of the materials. 

The pore structure of a solid can contribute to the disintegration, dissolution, adsorption, and diffusion of a drug material [26,27]. Because of this, porosity and pore size distribution measurements have been used extensively to study tablets [28-30], granules [31,32], and excipients [33]. The following classification system of pore sizes has been developed based on the average pore radii [6] ... 

Fig. 3.3.1. Electrical resistance as a function of temperature. Upper excipient solution lower solution with factor VIII. Cooling rate 15 °C/min. Measurements for [3.23], not published.

Dobutaraine hydrochloride may be determined spectrophotometrically in 0.5 M hydrochloric acid at the maximum of 278 nm. If excipients interfere, the drug may be extracted into ethyl acetate from pH 9 buffer followed by extraction into 0.5 M hydrochloric acid for the UV measurement. 

Halcinonide has been quantitated in various formulations or as bulk powder by a differential ultraviolet, borohydride reduction assay. 2 This differential assay involves measuring the ultraviolet absorbance of an aliquot of methanolic steroid solution containing sodium borohydride decomposed prior to the addition of steroid. Its absorbance is determined against a methanolic reference solution of steroid reduced by sodium borohydride to destroy the 3-one-4-ene chromophore. The utility of this procedure is that many interferences from excipients and other, unconjugated, steroids can be eliminated in the assay of a formulation. 

A method recommended for adoption as official, first action (27). The method in which methimazole is separated from tablet excipients by column chromatography on Celite 545 with chloroform as the eluent and then quantitatively measured and identified by IR spectrophotometry. This method was studied collaborative-ly by 10 analysts average recoveries from two simulated and two tablets mixtures ranged from 96.6% + 1.0 to 101.1% + 0.9 (28). 

The excipients present in pharmaceutical formulations can and often do interfere with quantitation of APIs, limiting the applications of direct UV-vis measurement for analyzing formulated products due to its lack of specificity. To minimize the interference of excipients, colorimetric methods based on chemical reactions have been used for rapid determination of drug substances in pharmaceutical formulations although their role in pharmacopoeias has been greatly reduced.117-122... 

To continue the investigation, carbon detected proton T relaxation data were also collected and were used to calculate proton T relaxation times. Similarly, 19F T measurements were also made. The calculated relaxation values are shown above each peak of interest in Fig. 10.25. A substantial difference is evident in the proton T relaxation times across the API peaks in both carbon spectra. Due to spin diffusion, the protons can exchange their signals with each other even when separated by as much as tens of nanometers. Since a potential API-excipient interaction would act on the molecular scale, spin diffusion occurs between the API and excipient molecules, and the protons therefore show a single, uniform relaxation time regardless of whether they are on the API or the excipients. On the other hand, in the case of a physical mixture, the molecules of API and excipients are well separated spatially, and so no bulk spin diffusion can occur. Two unique proton relaxation rates are then expected, one for the API and another for the excipients. This is evident in the carbon spectrum of the physical mixture shown on the bottom of Fig. 10.25. Comparing this reference to the relaxation data for the formulation, it is readily apparent that the formulation exhibits essentially one proton T1 relaxation time across the carbon spectrum. This therefore demonstrates that there is indeed an interaction between the drug substance and the excipients in the formulation. 

Neupogen), a four-helix bundle cytokine, is formulated at pH 4 but has been shown to maintain both thermal stability and tertiary structure at pH 2.60 In fact, the secondary structure of this molecule was shown to remain highly helical at pH 4 (Tm approximately 62°C) and 2 (Tm approximately 63°C) as compared to pH 7 (Tm approximately 55°C) where a less conformationally stable form was observed. In the same study, FTIR and CD data corroborated the tendency of the protein to unfold as measured by the loss of helical structure in the order pH 7 > pH 4 > pH 2. Moreover, after determining optimal pH conditions of thermostability, several studies have shown that excipient screening at such conditions can successfully predict the rank of formulation cocktails that offer the most favorable stability.14 23 31 56... 

---