Liquisolids as a platform for the formulation of cannabis tablets

Abstract

Mesoporous silica-based liquisolids offer an effective method for transforming liquid or sticky actives, such as cannabis extracts, into free-flowing powders. This approach broadens the formulation strategies available for these actives, which are typically limited to liquid formulations or soft gelatin encapsulation, by facilitating the formulation of tablets. However, tableting liquisolids is challenging due to issues including low tensile strength, capping and delamination. Overcoming these challenges requires careful selection of excipients and tableting parameters to produce tablets with sufficient tensile strength while also maintaining high Overall Liquid Load. In our study, we utilized a 65/35 volumetric ratio of 0.75 mL/g liquid loaded Syloid® XDP 3050 silica and Vivapur® 101 as a binder/filler to formulate cannabis liquisolid tablets with a target THC dose of 10 mg per tablet. Findings indicated that a 4% concentration of Kollidon® CL-F was optimal for disintegration, while 0.5% magnesium stearate proved to be the most effective lubricant concentration. Utilizing a rotary press compaction cycle on a StylOne® compaction simulator, we found precompression around half the main compaction pressure allowed for maximizing tableting speed while maintaining high tensile strength and keeping tablet defects to a minimum. The resulting cannabis liquisolid tablets demonstrated a tensile strength of 1.58 N/mm² and a high Overall Liquid Load of 38.4% (V/V). They exhibited acceptable disintegration time, friability, dissolution behavior and were proven to remain stable for 30 days at 40 °C and 0% humidity. Under refrigerated conditions, stability is predicted to be >3 years.

Introduction

In many countries, the medical use of cannabis has been legalized and liberalized, while some states have even decriminalized or legalized the use of cannabis for recreational purposes (Bahji and Stephenson, 2019). In practice today, cannabis medicines are mainly prescribed for chronic and cancer-related pain (McDonagh et al., 2022), multiple sclerosis (Nielsen et al., 2018) and anorexia/wasting (AbbVie Inc, 2017; Rosager et al., 2021). However, there are numerous other diseases for which cannabis medicines are used, or where beneficial effects are discussed in literature. These include but are not limited to cognitive impairment (Bilkei-Gorzo et al., 2017), migraine (Cuttler et al., 2020) or insomnia (Kuhathasan et al., 2022).

Over 400 active compounds in cannabis are described in literature (Pattnaik et al., 2022; Peschel and Politi, 2015), with the main actives being the psychoactive cannabinoid delta-9-tetrahydrocannbinol (THC) and non-psychoactive cannabidiol (CBD), which are produced upon heating the naturally more plentiful corresponding acids delta-9-tetrahydrocannbinolic acid (THCA) and cannabidiolic acid (CBDA) (ElSohly et al., 2017).

For treatment, physicians and patients can choose from a range of dosage forms. Dried cannabis flowers can be utilized in a manner similar to recreational consumption. However, this approach has the disadvantages of carrying social stigma (Reid, 2020) and making it challenging to determine and replicate a precise dose, as the smoking process is highly variable (Azorlosa et al., 1995; Lindgren et al., 1981). Consequently, cannabis extracts are frequently used. These extracts are produced from cannabis flowers using various extraction techniques, such as the use of different organic solvents. These can be used in vaporizers, which generally results in higher blood THC-levels compared to traditionally smoked cannabis (Spindle et al., 2018).

In contrast to inhalation, the onset of action is significantly delayed when cannabis medicines are administered orally, making this approach more suitable for long-term application. Cannabis extracts tend to be resinous/highly viscous and sticky in their undiluted form (Kebede et al., 2022), which limits processing and hinders the production of common oral dosage forms such as tablets. Currently, the only formulation option available for a single-dose oral dosage form is the manufacture of liquid-filled soft gelatine capsules like Marinol®, containing 2.5, 5 or 10 mg of synthetic THC (Dronabinol). Additionally, oral solutions like Syndros® and oromucosal sprays like Sativex® are also available.

As soft gelatin encapsulation is a highly specialized process, requiring dedicated machines and qualified employees, a cheaper and more mass producible single-dose oral dosage form for cannabis extracts and other resinous actives is desirable. A possible solution to this problem is the utilization of liquisolids. Here, a liquid or predissolved active is combined with adsorbent material to create an apparently dry, non-adherent powder, which can subsequently be formulated into a tablet or filled into a hard capsule.

This approach was first described by Spireas et al. (Spireas et al., 1992), who utilized microcrystalline cellulose in combination with colloidal silica as the adsorbent material. Since then, many authors report utilization of this technique to improve in vitro solubility of many APIs, including but not limited to carbamazepine (Javadzadeh et al., 2007), prednisolone (Spireas and Sadu, 1998), naproxen (Tiong and Elkordy, 2009) and simvastatin (Elkadi et al., 2017). Jaipakdee et al. already successfully formulated a cannabis extract into tablets using the liquisolid approach. Their work mainly focused on the dissolution performance of different liquid vehicles, with tablets produced using a hydraulic press. No lubricant or disintegrant was included in their formulation, leading to increasing disintegration times after storage. Furthermore, the compacts produced were notably large in size, due to the low maximum liquid load of the formulations used in the study (Jaipakdee et al., 2022).

Like the investigation by Jaipakdee et al., studies of liquisolids mostly focus on formulation parameters like excipient selection, excipient ratios and the influence of various liquid vehicles. They mainly utilize very simple equipment like hydraulic presses, and even if advanced equipment like a rotary tablet press is used, important parameters such as tableting speed are rarely reported. Among >110 screened publications on “liquisolid compacts” found using scopus, no systematic evaluation of parameters like tableting speed, precompression pressure, dwell time, lubricant concentration and lubricant blending time could be identified, even as these parameters are critical to industrial scale production. To establish liquisolids as a viable industrial production technique, these factors must be investigated as an initial step toward assessing the scalability of liquisolid compacts.

In a previous study, we outlined the compression characteristics of liquisolids containing Syloid® XDP 3050 mesoporous silica and optimized binary mixtures of silica with common binders/fillers to achieve maximum Overall Liquid Load. A volumetric mixture of 30% Vivapur® 101 and 70% 0.75 mL/g liquid loaded Syloid® XDP 3050 was found to produce tablets of sufficient tensile strength while maintaining an Overall Liquid Load of 36–41% [VLiquid/VTablet] with various liquid vehicles (Appelhaus et al., 2024). Continuously improving this optimized binary mixture, our study now aims to systematically evaluate the effects of disintegrant concentration, lubricant concentration, lubricant blending time, precompression pressure and tableting speed on liquisolid formulations. Subsequently, we intend to leverage these findings to formulate a sticky cannabis extract into a high drug load, mass producible and stable cannabis tablet containing 10 mg of THC.

Download the full article as PDF here Liquisolids as a platform for the formulation of cannabis tablets

or continue reading here

Materials

Dried cannabis flowers of the variety Pedanios 8/8 (Aurora Cannabis Enterprises Inc., Canada) were extracted using absolute ethanol (VWR International S.A.S., France). The extract was diluted using propylene carbonate (VWR International S.A.S., France). Syloid® XDP 3050 (Grace GmbH, Germany) was utilized as the mesoporous silica. The excipients microcrystalline cellulose (Vivapur® 101, JRS Pharma GmbH & Co. KG, Germany), crospovidone (Kollidon® CL-F, BASF SE, Germany) and magnesium stearate (Ligamed® MF-2 V, Peter Greven GmbH & Co. KG, Germany) were kindly donated by their respective manufacturers. HPLC grade acetonitrile (VWR International S.A.S., France) and trifluoroacetic acid (Merck KGaA, Germany) were used as eluents for the HPLC system. THC and CBD standard solutions (Sigma Aldrich Chemie GmbH, Germany) were analyzed to identify the respective substances. Sodium taurocholate hydrate (ThermoFischer GmbH, Germany), sodium chloride (Fischer Scientific, United Kingdom) and glacial acetic acid (VWR International S.A.S., France) were utilized to create the FeSSIF-V1 buffer solution. 1-Decanol (ThermoFischer GmbH, Germany) was employed as the acceptance layer in the BiPha+ apparatus. For the stability study, glass containers and respective twist-off lids (RIXIUS AG, Germany) as well as Microbag Tyvek® silica desiccant packages (Strobel GmbH, Germany) were utilized. Disodium mono‑hydrogen phosphate heptahydrate (Na2HPO4·7H2O, VWR International S.A.S., France) and monosodium dihydrogen phosphate monohydrate (NaH2PO4·H2O, VWR International S.A.S., France) were utilized to create phosphate buffer.

Jan Appelhaus, Karl G. Wagner, Kristina E. Steffens, Liquisolids as a platform for the formulation of cannabis tablets, International Journal of Pharmaceutics: X, Volume 11, 2026, 100508, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2026.100508.