Study Cimetidine

The following Case Studies show several examples of isosteres and bioisosteres in use. The story of the development of cimetidine also demonstrates the use of chain homologation. 

The assay used throughout the development of cimetidine was an animal assay on anesthetized rats. The rats were treated with histamine (11.36) to stimulate acid secretion. The same rats were then treated with a potential antagonist. Increases in stomach pH caused by administration of the antagonist were monitored to screen for activity. 

While an antagonist does not necessarily bind a receptor at the same site as an agonist, the agonist is 

With the failure of burimamide, the SK F team turned its attention to the other side of the molecule— the electronics of the imidazole ring. At biological pH, 

SCHEME 11.4 Conformational effects of a 5-methyl group in imidazoles 

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Information seems to be limited to the reports cited. The most likely explanation for the discord between the cimetidine/suxamethonium results is that in the one study reporting increased suxamethonium effects some of the patients were also given metoclopramide, which can inhibit plasma cholinesterase and prolong the effects of suxamethonium (see also Neuromuscular blockers + Metoclopramide , p.l27). In four other studies, cimetidine and other H2-receptor antagonists did not alter suxamethonium effects. Therefore, it seems unlikely that an interaction exists. There is some evidence that cimetidine may slightly prolong the effects of vecuronium, but ranitidine appears not to interact. Atracurium and rocuro-nium appear not to be affected. Overall these possible interactions seem to be of little clinical significance. 

A single 500-mg dose of mefloquine was given to 10 healthy subjects before and after they took cimetidine 400 mg twice daily for 28 days. The ci-metidine had no effect on the AUC or serum levels of mefloquine, but its half-life increased hy 50% (liom 9.6 to 14.4 days) and the oral clearance decreased hy almost 40%. In another study mefloquine was given to 6 healthy subjects and 6 patients with peptic ulcers, before and after cimetidine 400 mg twice daily for 3 days. In contrast to the first study, cimetidine increased the maximum plasma levels of mefloquine by about 42% and 20% and increased the AUC by about 37% and 32% in the healthy subjects and patients, respectively. The elimination half-life was increased, but not to a significant extent. ... 

In a preliminary report of a study, 4 days of treatment with cimetidine [dose not stated] in 11 healthy subjects had a small effect on the pharmacokinetics of tocainide 500 mg given intravenously over 15 minutes, whieh was not considered elinieally important. In another study, cimetidine 300 mg four times daily for 2 days reduced the AUC of a single 400-mg oral dose of toeainide in 7 healthy subjects by about one-third. The peak... 

This interaction has been described in many reports and studies involving patients and healthy subjects. "" Phenytoin toxicity has developed in some individuals. The extent of the rise in serum levels is very variable being quoted as 13 to 33% over about 6 days in one report and 22 to 280% over 3 weeks in others." There is some evidence that the effect may be dependent on cimetidine dose. One study found that the effect of cimetidine 2.4 g daily was greater than that of 1.2 g daily or 400 mg daily, which did not differ from each other. In another study, cimetidine 200 mg twice daily for 2 weeks had no effect on serum phenytoin levels in 9 patients taking stable doses of phenytoin. ... 

In a study in 12 healthy subjects cimetidine had no significant effect on the conversion of single 20-mg doses of ebastine to its active metabolite carebastine, and there was no evidence of sedation or other adverse effects. In this study cimetidine was given as 2 g in divided doses the day before the ebastine dose and 400 mg four times daily both on the day of and the day after the ebastine dose. ... 

Cimetidine 1 g daily in divided doses increased the AUC and peak plasma levels of pindolol 10 mg twice daily by 30% and 33%, respectively, although these changes were not statistically significant. In another study, cimetidine 400 mg twice daily increased the AUC of the pindolol by about 40% and decreased the renal elearance by about 35%. ... 

Reports are inconsistent. Cimetidine and famotidine have been reported to increase cielosporin levels, whereas in other studies cimetidine, famotidine and ranitidine have been reported to not affect cielosporin levels. Both cimetidine and ranitidine have been reported to cause an increase in serum creatinine levels, in some but not all studies, but this may possibly not be a reliable indicator of increased nephrotoxicity. Isolated cases of thrombocytopenia and hepatotoxicity have been reported with ranitidine and cielosporin. 

In 5 subjects cimetidine I g daily for 6 days increased the half-life of a single 300-mg dose of caffeine by about 70% and reduced caffeine clearance. In another study, cimetidine 1.2 g daily for 4 days increased the caffeine half-life by 45% in 6 smokers and by 96% in 6 non-smokers. The caffeine clearance was reduced by 31% in the smokers and by 42% in the non-smokers. A further study found that the caffeine half-life was increased by 59% and the clearance decreased by 40% by cimetidine. Conversely, in a further study in children, cimetidine was not found to affect caffeine metabolism as assessed by the caffeine breath test. ... 

In another study cimetidine 600 mg twice daily was found to double the steady-state plasma levels of doxepin 50 mg daily, whereas ranitidine 300 mg daily had no effect. A patient taking doxepin complained that the normally mild adverse effects (urinary hesitancy, dry mouth and decreased visual acuity) became incapacitating when he also took cimetidine. His serum doxepin levels were found to be elevated. ... 

There is a risk of acute renal failure when iodi-nated contrast material that is used for radiological studies is administered with metformin. Metformin therapy is stopped for 48 hours before and after radiological studies using iodinated material. Alcohol, amiloride, digoxin, morphine, procainamide, quini-dine, quinine ranitidine, triamterene, trimethoprim, vancomycin, cimetidine, and furosemide all increase the risk of hypoglycemia. There is an increased risk of lactic acidosis when metformin is administered with the glucocorticoids. 

Hj-antagonists alone, such as cimetidine or ranitidine, have a modest effect on cutaneous flush reaction and maybe also on the heart [14, 52]. However, when applied they should be given together with Hj-antagonists. There are some studies showing a beneficial effect of combined H - and Hj-antagonist treatment or pretreatment in anaphylaxis [46, 53]. 

Thorens J, Froehlich F, Schwizer W, Saraga E, Bille J, Gyr K, et al Bacterial overgrowth during treatment with omeprazole compared with cimetidine A prospective randomised double blind study. Gut 1996 39 54-59. 

This final Pures step is the last stage of manufacture for the API and may be considered as the API Product design step. It will be the focus of this chapter s case study, using the generic drug molecule Cimetidine as an example. 

In the monotropic case the relative solubility of the two polymorphs does not change with temperature if Form I is the most stable and least soluble at low temperatures then it will also be the same at all other temperatures, Figure 3. An example of this behavior is the Cimetidine Form A and B relationship presented in the case study of section 6. 

In the enantiotropic case the relative solubility and stability changes at a specific transition temperature where the two solubility curves cross. A given polymorph may be more soluble (less stable) above the transition point, but less soluble below and vice versa, Figure 4. An example of this relationship is the Form C and A or B relationships for Cimetidine in the case study. 

Whenever the solubility curve is crossed for the less stable Form II there is a risk that it will nucleate and contaminate the product. This situation is very probable when the solubility curves of the two polymorphs lie close together, as shown in Figure 21 of the Cimetidine case study. The addition of seed crystals of Form I, close to its solubility curve, and minimization of the supersaturation during the growth process is a good method of control in this instance. Solvent selection to extend the width of the Form II metastable zone would also be desired, as discussed in section 2.4.4. 

The non-random two-liquid segment activity coefficient model is a recent development of Chen and Song at Aspen Technology, Inc., [1], It is derived from the polymer NRTL model of Chen [26], which in turn is developed from the original NRTL model of Renon and Prausznitz [27]. The NRTL-SAC model is proposed in support of pharmaceutical and fine chemicals process and product design, for the qualitative tasks of solvent selection and the first approximation of phase equilibrium behavior in vapour liquid and liquid systems, where dissolved or solid phase pharmaceutical solutes are present. The application of NRTL-SAC is demonstrated here with a case study on the active pharmaceutical intermediate Cimetidine, and the design of a suitable crystallization process. 

Case Study - Solubility Modelling and Crystallization Process Design for Cimetidine... 

Cimetidine is known to crystallize in 5 polymorphic forms and 3 hydrated forms [11]. Solubility data is presented in this reference for Forms A, B and C. Form E was not known at the start of the study in reference [11] and Form D could not be crystallized, suggesting that it is less stable than the other forms. This is confirmed by melting point data which indicates the order of thermodynamic stability close to the melting temperature isEmelting point data for the evaluated forms are presented in Table 3. Form A is the commercially available Form and the desired product for this case study. 

For the purpose of this case study we will select Isopropyl alcohol as the crystallization solvent and assume that the NRTL-SAC solubility curve for Form A has been confirmed as reasonably accurate in the laboratory. If experimental solubility data is measured in IPA then it can be fitted to a more accurate (but non predictive) thermodynamic model such as NRTL or UNIQUAC at this point, taking care with analysis of the solid phase in equilibrium. As the activity coefficient model only relates to species in the liquid phase we can use the same model with each different set of AHm and Tm data to calculate the solubility of the other polymorphs of Cimetidine, as shown in Figure 21. True polymorphs only differ from each other in the solid phase and are otherwise chemically identical. 

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