The application of gas chromatography/atmospheric pressure chemical ionisation time-of-flight mass spectrometry to impurity identification in Pharmaceutical Development.

Accurate mass measurement (used to determine elemental formulae) is an essential tool for impurity identification in pharmaceutical development for process understanding. Accurate mass liquid chromatography/mass spectrometry (LC/MS) is used widely for these types of analyses; however, there are still many occasions when gas chromatography (GC)/MS is the appropriate technique. Therefore, the provision of robust technology to provide accurate mass GC/MS (and GC/MS/MS) for this type of activity is essential. In this report we describe the optimisation and application of a newly available atmospheric pressure chemical ionisation (APCI) interface to couple GC to time-of-flight (TOF) MS.To fully test the potential of the new interface the APCI source conditions were optimised, using a number of standard compounds, with a variety of structures, as used in synthesis at AstraZeneca. These compounds were subsequently analysed by GC/APCI-TOF MS. This study was carried out to evaluate the range of compounds that are amenable to analysis using this technique. The range of compounds that can be detected and characterised using the technique was found to be extremely broad and include apolar hydrocarbons such as toluene. Both protonated molecules ([M + H](+)) and radical cations (M(+.)) were observed in the mass spectra produced by APCI, along with additional ion signals such as [M + H + O](+).The technique has been successfully applied to the identification of impurities in reaction mixtures from organic synthesis in process development. A typical mass accuracy of 1-2 mm/zunits (m/z 80-500) was achieved allowing the reaction impurities to be identified based on their elemental formulae. These results clearly demonstrate the potential of the technique as a tool for problem solving and process understanding in pharmaceutical development. The reaction mixtures were also analysed by GC/electron ionisation (EI)-MS and GC/chemical ionisation (CI)-MS to understand the capability of GC/APCI-MS relative to these two firmly established techniques.

Pharmaceutical quality evaluation of lipid emulsions containing PGE1: alteration in the number of large particles in infusion solutions.

There are two generics of a parenteral lipid emulsion of prostaglandin E1 (PGE(1)) (Lipo-PGE(1)) in addition to two innovators. It was reported the change from innovator to generic in clinical practice caused the slowing of drip rate and formation of aggregates in the infusion line. Thus, we investigated the difference of pharmaceutical quality in these Lipo-PGE(1) formulations. After mixing with some infusion solutions, the mean diameter and number of large particles were determined. Although the mean diameter did not change in any infusion solutions, the number of large particles (diameter >1.0 microm) dramatically increased in generics with Hartmann's solution pH 8 or Lactec injection with 7% sodium bicarbonate. Next, we investigated the effect of these infusion solutions on the retention rate of PGE(1) in lipid particles. The retention rate of PGE(1) in these two infusion solutions decreased more quickly than that in normal saline. Nevertheless, there were no significant differences among the formulations tested. Our results suggest that there is no difference between innovators and generics except in mixing with these infusion solutions. Furthermore, that monitoring the number of large particles can be an effective means of evaluating pharmaceutical interactions and/or the stability of lipid emulsions.

[Alprostadil Reference Standard (Control 001) of National Institute of Health Sciences].

The raw material of Alprostadil was examined for the preparation of "Alprostadil Reference Standard (Control 001)". Analytical data obtained were: IR spectrum, same as that of the Alprostadil Reference Standard (Control 923); thin-layer chromatography, no impurities were detected until 20 micrograms; high-performance liquid chromatography (HPLC), total amount of impurities estimated to be less than 0.2%. Based on the above results, the raw material was authorized as the Japanese Pharmacopoeia Alprostadil Reference Standard (Control 001).

Oral misoprostol versus vaginal gemeprost for cervical dilatation prior to vacuum aspiration in women in the sixth to twelfth week of gestation.

The effectiveness of oral misoprostol versus vaginal gemeprost for cervical dilatation prior to vacuum aspiration was compared in women in the 6th to 12th week of pregnancy. Sixty-four nulliparous women requesting termination of pregnancy between 6th to 12th weeks of gestation were randomized to receive either 400 micrograms misoprostol orally or 1 mg vaginal gemeprost at 12 hr or 3 hr prior to vacuum aspiration, respectively. The cervical dilatation at vacuum aspiration, the ease of the subsequent surgical procedure, and the incidence of complications and side effects were compared between these two methods of cervical priming. The median cervical dilatation at vacuum aspiration in the misoprostol group was significantly greater than that in the gemeprost group (8.0 mm versus 7.0 mm, p < 0.02). Preoperative side effects were significantly less frequent in the misoprostol group (p < 0.01). The ease of dilatation assessed subjectively by the operating surgeons was also improved significantly in the misoprostol group (p < 0.01). However, the duration of operation and blood loss were similar in both groups. Since misoprostol is also much cheaper and more convenient to use, we conclude that oral misoprostol is better than vaginal gemeprost for cervical dilatation prior to vacuum aspiration in first trimester pregnancy.

PIP: Given the importance of adequate cervical dilatation to vacuum aspiration abortion, the effectiveness of oral misoprostol and vaginal gemeprost was compared. The 64 study subjects, all in the first 6-12 weeks of pregnancy, were randomly assigned either to take 400 mcg of misoprostol the night before pregnancy termination or were given 50 mg of vitamin B6 (placebo for misoprostol) to be taken the night before the procedure followed by vaginal insertion of 1 mg of gemeprost three hours preoperatively. Preoperative side-effects--nausea, vomiting, abdominal pain, and vaginal spotting--were significantly greater (p 0.01) in the gemeprost group; 28 out of 32 women in the misoprostol group compared to only 17 out of 32 in the gemeprost group experienced no side effects. The mean baseline cervical dilatation of 8.1 mm in the misoprostol group was significantly greater (p 0.01) than that in the gemeprost group (7.0 mm) and the ease of further dilatation was rated by surgeons as easier than normal for 87.5% of women in the former group compared to 59.4% in the latter group (p 0.01). The duration of the procedure and mean blood loss were similar in both groups. In addition to being more effective than gemeprost, misoprostol is less expensive and stable at room temperature. This is the first prospective, randomized study of oral as opposed to vaginal administration of misoprostol for cervical dilatation.

[The Alprostajil Reference Standard (Control 921) of the National Institute of Health Sciences].

Raw alprostajil material was examined for preparation of the "Alprostajil Reference Standard (Control 921)". Analytical data obtained were as follows: infrared spectrum, the same as that of the USP Alprostajil Reference Standard; thin-layer chromatography, no impurities were detected up to 20 micro g; high-performance liquid chromatography (HPLC), no impurities were detected; assay result, 99.6% by HPLC. Based on the above findings, this raw material was authorized as the NIHS Alprostajil Reference Standard (Control 921).