(T0930-03-14) Toward Enhanced Solubility of Cannabidiol: Preparation and Evaluation of Cannabidiol Solid Dispersions Using Vacuum Compression Molding and Cryogenic Milling

Purpose: It is known that cannabidiol (CBD) presents low bioavailability, estimated at 6% and explained by the drug’s poor solubility (1). The present study aims to develop and characterize CBD amorphous solid dispersion (ASD) using Vacuum Compression Molding (VCM) and cryogenic milling. Amorphization of CBD is expected to enhance the drug solubility and its release.

Methods: Solid dispersions of CBD and polymers were performed using Vacuum Compression Molding (VCM, MeltPrep, East Setauket, NY, USA) and Cryogenic Milling (SPEX 6700, FREEZER/MILL, Metuchen, NJ, USA). For both methods, 5% w/w of CBD was mixed with 5% w/w of poloxamer 188 and 90% w/w polymeric carrier (Polyethylene Oxide, PEO-N80 or Hydroxypropyl cellulose, HPC-EF) using a mortar and pestle. 300 mg of physical mixture was added to the VCM chamber. The physical mixture was heated at 130°C for 4 min and then cooled using compressed air. Discs of 20 mm diameter were collected to obtain formulations (F1V, F2V). For the solid dispersion preparation using Freezer/Mill, five grams of each physical combination were introduced to the grinder vial of the Freezer/Mill. Following the addition of liquid nitrogen, three 3-minute cycles were completed, followed by a 2-min break after each cycle. Then, 300 mg of the fine powder obtained was weighed and utilized to create a solid dispersion formulation (F1C, F2C). Formulation compositions of each solid dispersion formulation are shown in (Table 1). The thermal stability of CBD was evaluated using Thermogravimetric Analysis TGA 55 (TA Instruments, New Castle, DE, USA). The formulations were further characterized using differential scanning calorimetry, DSC 25 instrument (TA Instruments, Newcastle, DE, USA) and scanning electron microscopy, SEM (JEOL, Peabody, MA, USA). Fourier- Transform Infrared Spectroscopy, FTIR ATR (Agilent Technologies, Santa Clara, CA, USA) was performed to investigate interactions between the drug and polymeric carriers. In vitro dissolution testing of pure CBD and formulations were evaluated using USP apparatus II. 900 mL of phosphate buffer pH 7.4 with 0.1% v/v tween 80, at 37°C and 100 rpm.

Results: Formulations were processed successfully using VCM and cryo-milling. TGA showed that CBD degradation starts occurring after 200°C which is above the VCM processing temperature. FTIR spectra of formulations showed disappearance of the bands corresponding to (O-H) and (C=C) stretching which may indicate hydrogen interactions and hydrophobic interactions between the drug and polymers. DSC thermograms of F1V and F1C formulations (Figure 1) showed thermal peaks at 65°C which could indicate the presence of CBD or PEO N80 in crystalline form since they both present very close melting points. F2V and F2C did not show any of the thermal event peaks which is explained by the conversion of the drug to the amorphous state. Images from the SEM (Figure 2) demonstrated that the two formulations had a smooth surface, confirming that the formulations had transformed into the amorphous state. In vitro drug release was performed and continued for 4 hours. The release profile showed increase in cannabidiol’s dissolution rate by respectively 4.48 and 4-fold for formulations containing PEO-N80 and 3.3 and 4.76-fold for formulations containing HPC-EF in four hours.

Conclusion: In this study, solid dispersions of CBD formulations with HPC-EF and PEO-N80 were successfully achieved using both the VCM technology, and cryogenic milling. Formulations were prepared and solid-state characterizations were performed and confirmed the amorphization of CBD. In vitro drug release confirmed the efficiency of the two methods to increase cannabidiol’s solubility and dissolution rate.

References: (1) Koch N, Jennotte O, Gasparrini Y, Vandenbroucke F, Lechanteur A, Evrard B. Cannabidiol aqueous solubility enhancement: Comparison of three amorphous formulations strategies using different type of polymers. Int J Pharm. 2020 Nov 15;589:119812. doi: 10.1016/j.ijpharm.2020.119812. Epub 2020 Aug 31. PMID: 32882367.


Table1. Solid dispersion methods and formulations


Figure1. DSC and FTIR analyses of pure CBD and formulations


Figure2. SEM images of pure CBD, F1C, F2C, F1V and F2V formulations