Diltiazem preparations

K. Murata, H. Yamahara, M. Kobayashi, K. Noda, and M. Samejima, Pharmacokinetics of an oral sustained-release diltiazem preparation. J Pharm Sci 78 960-963 (1989). 

K. Murata and K. Noda, Pharmacokinetic analysis of an oral sustained-release diltiazem preparation using multifraction absorption models. Pharm Res 10 757-762 (1993). 

Preparation of calcium antagonist diltiazem, derivative of 2,3-dihydro-4//-l,4-benzothiazepinone 99YGK394. 

Benzothiazepines belong to the three classes of calcium channel blockers which are important cardiovascular drugs in the management of angina pectoris and hypertension. A diastereoselective one-pot synthesis of the trans-and ds-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-l,5-benzothiazepin-4-one nucleus, a key intermediate in the preparation of the calcium channel blocker Diltiazem, was carried out under microwave irradiation in an open vessel (Scheme 25). Control of the diastereoselectivity was achieved by vary-... 

The pharmacological activity of the 1,5-benzothiazepine derivative diltiazem has given further impetus for synthetic routes to this ring system. A traditional preparation of the intermediate 62 by the reaction sequence shown in Scheme 12 has been subject to microwave studies, when the final product was obtained as a mixture of isomers <96TL6413>. Under optimised conditions irradiation in toluene at 390 watts for 20 minutes gave mainly the cis-isomer as the main product (cis/trans 9 1) in 75% yield. However, reaction at 490 watts in the presence of acetic acid resulted in a reversal of this ratio and a yield of 84%. The... 

Biochemical studies with purified preparations incorporated into liposomes have also been performed [32,33,96-98]. Reconstituted receptors from skeletal muscle bound DHPs, PAAs and diltiazem with high affinity and in a 1 1 1 stoichiometry [97], In general, the reconstituted proteins exhibit the characteristic pharmacological properties expected for these channels. In recent studies, our laboratory has reconstituted partially purified channels into liposomes containing the Ca -sensitive fluorescent dye, fluo-3 [33,96]. These channels exhibit Ca influx that is sensitive to activation by Ca channel activators and inhibitors with affinities similar to those observed in intact cells, and the Ca influx is dependent on the establishment of a gradient in the presence of valinomycin [132]. This assay provides a convenient and rapid approach to obtaining a macroscopic picture of the activity of the channels under different conditions, while the more complex studies in lipid bilayers provide a more complete analysis of the single channel behavior. 

Zentner and coworkers [24,26] utilized this information in their development of a system that releases this drug over a 24 hr period. The use of NaCl to modulate the release of diltiazem presents an interesting problem in that the concentration of the solubility modifier must be maintained within certain limits and below its saturation solubility within the device. To solve this problem, core formulations were developed that contained both free and encapsulated NaCl. The encapsulated NaCl was prepared by placing a microporous coating of cellulose acetate butyrate containing 20 wt% sorbitol onto sieved NaCl crystals. The coated granules released NaCl over 12-14 hr period via an osmotic mechanism into either water or the core tablet formulation. The in vitro release profile for tablets (core I devices) containing 360 mg of diltiazem HC1 and 100 mg of NaCl equally divided between the immediate release and controlled release fractions... 

All chemicals were used as received. PDADMAC and PAMPS were obtained from Aldrich Chemical Co. (Milwaukee, WI). Diclofenac sodium, sodium sulfathiazole, labetalol HCl, propranolol HCl, verapamil HCl, and diltiazem HCl were purchased from Sigma Chemical (St. Louis, MO). Dextrose USP was obtained from Amend Co. (Irvinton, NJ). Water was distilled and deionized using a Nanopure purihcation system (Fischer Scientihc, Fair Lawn, NJ). Simulated intestinal fluid was prepared using a O.OIM phosphate buffer (sodium phosphate monobasic and potassium phosphate dibasic) at pH 7 and 5.5 with different amounts of NaCl to vary the ionic strength. Simulated gastric fluid (pH 1.5) was prepared with concentrated HCl with different amounts of NaCl to vary the ionic strength. 

A pharmacist asked a clinical pharmacist for information about Cartia . Because an electronic drug reference listed the active ingredient as aspirin, the pharmacist was prepared to substitute an aspirin product for Cartia . The clinical pharmacist recognized the new product as Cartia XT (Diltiazem, a calcium channel blocker) and prevented the error. 

In an approach to the potent calcium antagonist, diltiazem (11), a BINOL-derived ketone (12) was found to provide higher ee than when a carbohydrate-derived ketone was used to prepare the epoxide 13 (Scheme 9.16).123... 

Alternatively, diltiazem (30) has been prepared using the Evans auxiliary derivative 31 derived from L-valine (Scheme 23.7).55 After dehydration of the adduct from the condensation of 31 with anisaldehyde through the mesylate, the enol ether was formed with a Z E ratio of 4 1. This imide was then treated with 2-aminothiophenol in the presence of 0.1 equiv. 2-aminothiophenoxide with no change in the isomer ratio. The auxiliary was removed with trimethylaluminum, with concomitant formation of the lactam. After separation by crystallization, the correct diastereoisomer was converted to diltiazem in >99%ee. 

Follonier, N. Doelker, E. Cole, E.T. Various ways of modulating the release of diltiazem hydrochloride from hot-melt extruded sustained release pellets prepared using polymeric materials. J. Controlled Release 1995, 36, 243-250. 

Bayomi MA, al-Suwayeh SA, el-Helw AM, Mesnad AF. Preparation of casein-chitosan microspheres containing diltiazem hydrochloride by an aqueous coacervation technique. Pharma Acta Helv 1998 73 187-192. 

Although primarily used as a suspending agent, xanthan gum has also been used to prepare sustained-release matrix tablets. ° Controlled-release tablets of diltiazem hydrochloride prepared using xanthan gum have been reported to sustain the drug release in a predictable manner and the drug release profiles of these tablets were not affected by pH and agitation rate.< >... 

The exception to this is the case of some sustained-release preparations where the release properties of different brands may vary (for example modified-release diltiazem or theophylline preparations). In these cases, it is usual for patients to be maintained on one particular brand to prevent fluctuations in plasma concentration. See the British National Formulary for further details. 

A variety of synthetic approaches (both stereospecific and nonstereospecific) have been reported for diltiazem and diltiazem hydrochloride in the scientific literature (4, 5, 6, 7, 8, 9). Patent references for the preparation of the compound also exist in many countries, notably ... 

USA Patent No. 3,562,257 Germany Patent No. 1,805,714 Japan Patent No. 5,920,273 German Patent No. 3,415,035 and USA Patent No. 4,552,695. One approach (9) to stereospecific synthesis of diltiazem hydrochloride is shown in Figure 2. Diltiazem hydrochloride is prepared from (E)-methyl-4-methoxypropenoate ((1)] via either of the enantiomers of threo-methyl-3-(4-methoxyphenyl)-2,3-dihydroxypropanolate... 

Diltiazem hydrochloride is characterized by an absorption maximum at approximately 235 nm. This absorption can be used as the basis for the quantitative determination of diltiazem. The assay is performed by comparing the absorbance of the sample dissolved in 0.1 N HCI to a standard of a known concentration in 0.1 N HCI. The absorbance for the drug product is calculated by subtracting the absorbance of the excipients similarly prepared in 0.1 N HCI from the absorbance recorded for the drug product. 

SIL CN column (5 pm particle size, 150 mm x 4.6 mm I.D.) and a mobile phase of 0.05M aqueous potassium phosphate (monobasic) solution containing 0.05% (v/v) triethylamine (pH 4.0) acetonitrile (75 25). The separation is achieved at ambient temperature using a flow rate of 1.0 mL/minute. UV absorbance detection is accomplished at a wavelength of 236 nm. The standard and sample solutions are prepared in a diluent of acetonitrile and 20 pL are injected onto the column. The retention time of diltiazem is approximately 13 minutes while that of the potential degradation product, desacetyl diltiazem, is 9 minutes. The analysis is completed within 17 minutes and allows quantitation of both components. A typical HPLC chromatogram is shown in Figure 14. 

Fig. 11. Lipase. Enzymatic preparation of (27 ,3S)-phenyl glycidic esters, the key building-block of Diltiazem [139,140]...

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