Physicochemical characterization of berberine chloride: a perspective in the development of a solution dosage form for oral delivery

Abstract

The objective of the present research was to evaluate the physicochemical characteristics of berberine chloride and to assess the complexation of drug with 2-hydroxypropyl-β-cyclodextrin (HPβCD), a first step towards solution dosage form development. The parameters such as log P value were determined experimentally and compared with predicted values. The pH-dependent aqueous solubility and stability were investigated following standard protocols at 25°C and 37°C. Drug solubility enhancement was attempted utilizing both surfactants and cyclodextrins (CDs), and the drug/CD complexation was studied employing various techniques such as differential scanning calorimetry, Fourier transform infrared, nuclear magnetic resonance, and scanning electron microscopy. The experimental log P value suggested that the compound is fairly hydrophilic. Berberine chloride was found to be very stable up to 6 months at all pH and temperature conditions tested. Aqueous solubility of the drug was temperature dependent and exhibited highest solubility of 4.05 ± 0.09 mM in phosphate buffer (pH 7.0) at 25°C, demonstrating the effect of buffer salts on drug solubility. Decreased drug solubility was observed with increasing concentrations of ionic surfactants such as sodium lauryl sulfate and cetyl trimethyl ammonium bromide. Phase solubility studies demonstrated the formation of berberine chloride-HPβCD inclusion complex with 1:1 stoichiometry, and the aqueous solubility of the drug improved almost 4.5-fold in the presence of 20% HPβCD. The complexation efficiency values indicated that the drug has at least threefold greater affinity for hydroxypropyl-β-CD compared to randomly methylated-β-CD. The characterization techniques confirmed inclusion complex formation between berberine chloride and HPβCD and demonstrated the feasibility of developing an oral solution dosage form of the drug.

Fig. 1

Structure of berberine chloride with assigned proton signals

Fig. 2

Influence of surfactants at different concentrations on solubility of berberine chloride. Data represent the mean value (n = 3)

Fig. 3

Phase solubility diagram of berberine chloride in water. Values represent mean ± SD (n = 3)

Fig. 4

An overlay of DSC thermograms of berberine chloride, HPβCD, the inclusion complex, and their corresponding physical mixture

Fig. 5

An overlay of FTIR spectra of berberine chloride, HPβCD, and the inclusion complex

Fig. 6

¹HNMR spectra (400 MHz) of (1) berberine (25 mM), (2) HPβCD (25 mM), (3) berberine:HPβCD (4:1), and (4) berberine:HPβCD (1:4). Samples are dissolved in DMSO-d6 at 21°C

Fig. 7

Graphical representation of effect of HPβCD on berberine chloride. The chemical shifts are referenced by the residual solvent peak at 2.503 ppm

Fig. 8

a Scanning electron micrographs of berberine chloride. b Scanning electron micrographs of HPβCD. c Scanning electron micrographs of the drug-cyclodextrin inclusion complex