Effect of Compression on Interaction between 1,4-Dihydropyridine Compounds and Lactose Monohydrate

Abstract

1,4-Dihydropyridine type compounds such as Nifedipine and Nicardipine hydrochloride have antihypertensive activity, which are frequently used as a calcium channel antagonist. Especially, manidipine dihydrochloride and benidipine hydrochloride have the characteristics of more potent and longer acting than the other 1,4-dihydropyridines, which have been developed in the earlier time. 2,3)The drug molecules commonly have polymorphs and/or solvate forms whose solubility, stability and also bioavailability are well known to be different from their mother compounds. 4) In the series of 1,4-dihydropyridines, the existences of polymorph and/or hydrate form have been reported in nicardipine hydrochloride, 5) nilvadipine 6) and manidipine dihydrochloride. 2)We have reported in the previous paper 7) that the dissolution behaviors of anhydrate and monohydrate forms of benidipine hydrochloride, which is one of the 1,4-dihydropyridines and has a similar structure of manidipine dihydrochloride. We also have reported 8) that during thermal treatment of physical mixtures of manidipine dihydrochloride or benidipine hydrochloride with lactose monohydrate, the interaction was observed between them but not with lactose anhydrate. The water of crystallization in lactose monohydrate was clearly participated in this interaction and it was suggested that a portion of water molecule in lactose monohydrate migrated to these compounds during thermal treatment.Pharmaceutical preparation process consists of several processes such as manipulation, granulation, drying, compression and so on. Some medicinal compounds were reported that transformation of crystal form could occur by mechanical manipulation during these processes.9-11) The pharmaceutical formulations usually contain medicinal compounds and excipients. Therefore, the approach to discuss the interaction between drug molecules and excipient molecules induced by mechanical and also thermal energy during pharmaceutical process must be important in the formulation studies. In the present paper, the effect of compression process on the interaction between manidipine dihydrochloride or benidipine hydrochloride and lactose monohydrate during thermal treatment is described. ExperimentalMaterials Manidipine dihydrochloride (Sanyo Kagaku), benidipine hydrochloride (Daito), lactose monohydrate (DMV 200#), and magnesium stearate (Taiheikagaku) were used for preparation of tablets. Manidipine dihydrochloride was obtained as b-form and was used.Measurement of Particle Size Particle size of manidipine dihydrochloride (Man), benidipine hydrochloride (Ben) and lactose monohydrate (Lac) was measured by laser diffraction method (HEROS SYSTEM, Particle size analyzer, JEOL). Particle size was expressed as volume mean diameter (D 50 ).Preparation for Man and Ben Tablets The mixtures of Man or Ben with Lac in three different molar ratios were mixed with 1% or more amount of magnesium stearate (Mgst). Tablets each weighing 100 mg, flat-shaped, 8 mm in diameter, were prepared using a physical testing machin...

Effects of Compression on the Interaction between 1,4-Dihydropyridine Compounds and Lactose Monohydrate (II): Differences in Powder Properties of 1,4-Dihydropyridine Compounds

“…5) The endothermic peaks at 170°C were observed for all particle sizes of Lac and their area increased with the increase in compression force not only for Lac25 6) but also for Lac75 and Lac125. These results show that the interaction between Man and Lac during thermal treatment was accelerated by the mechanical energy of compression.…”

“…1,2) We described the dissolution behaviors of the anhydrate and monohydrate forms of Ben. 3,4) We also found that an interaction occurred during differential scanning calorimetry (DSC) measurements of physical mixtures of Man or Ben with lactose monohydrate (Lac), but no interaction was observed with lactose anhydrate.5) The water of crystallization in Lac was clearly participated in this interaction. Moreover, we investigated the effects of compression on this interaction and found that it was accelerated by compression and related to disruption of the Lac crystal structure.…”

“…1,2) We described the dissolution behaviors of the anhydrate and monohydrate forms of Ben. 3,4) We also found that an interaction occurred during differential scanning calorimetry (DSC) measurements of physical mixtures of Man or Ben with lactose monohydrate (Lac), but no interaction was observed with lactose anhydrate.…”

“…Moreover, we investigated the effects of compression on this interaction and found that it was accelerated by compression and related to disruption of the Lac crystal structure. 6) In the solid-state reaction, it is important to consider the particle size of compounds because the extent of the reaction may depend on the contact area of the particles. In the present study, the effects of the particle size of Lac on the interaction between Man or Ben and Lac relative to compression force were investigated and discuss the difference in the powder properties between Man and Ben.…”

Physical Characterization of Ibuprofen-Stearic Acid Binary Mixture Due to Compression Force

“…Tablet manufacturing process produces thermal and mechanical energy which possibly results in physical interaction amongst components used (Hosaka et al, 2005). During tablet compression, interaction can undergo between active substances, active substance with excipient, or between excipients.…”