Hot-melt extruded formulations screening
It's made easy with VCM.
Vacuum Compression Molding is the novel screening method for hot-melt extruded formulations. This innovative technology allows the preparation of thermoplastic dosage forms (e.g. ASDs or implants in the milligram to gram-scale), and it's the first lossless approach to melt material into a defined shape without air inclusions. Read on to discover VCM multiple applications, compare it with the most used screening techniques and boost your research in the lab!
Transparent VCM Discs
mg-to-g scale & no material loss
>g scale & high material loss
Solubility of Active Pharmaceutical Ingredients
According to IUPAC, solubility is the analytical composition of a saturated solution expressed as a proportion of a designated solute in a designated solvent. Solubility is one of the important parameters to achieve the desired concentration of drug in systemic circulation for an anticipated pharmacological response.
The Biopharmaceutics Classification System (BCS) is a guide for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration. This system restricts the prediction using the parameters solubility and intestinal permeability.
Classification System according to Pharmacopoeia
Solubility is based on the highest-dose strength of an immediate release product. A drug is considered highly soluble when the highest dose strength is soluble in 250 mL or less of aqueous media over the pH range of 1 to 7.5. The volume estimate of 250 mL is derived from typical bioequivalence study protocols that prescribe the administration of a drug product to fasting human volunteers with a glass of water. (Source: Ketan T. Savjani, Anuradha K. Gajjar, Jignasa K. Savjani, "Drug Solubility: Importance and Enhancement Techniques", International Scholarly Research Notices, vol. 2012, Article ID 195727, 10 pages, 2012. Link here).
Solubility of APIs in tablets
How long does it take to dissolve?
Let's consider some examples of poorly-soluble drugs according to Pharmacopoeia classification. Itraconazole has a solubility of 1 ng/ml and its typical dose is 100 mg of API. To dissolve this dose, a volume of around 100 l of water is required. For Fenofibrate, 205 L of water is required for dissolution. Formulations are usually tested in a dissolution tester (which mimics the gastrointestinal canal), and it only has standard volumes of less than 1 L. The low solubility of these complex molecules can be driven by poor dissolution or can be truly solubility-limited due to either the lipophilicity of the molecule or high crystal forces that inhibit dissolution. These types of compounds are often referred to as brick dust compounds.
Brick Dust compounds
Fenofibrate Solubility in Water: 0.707 ng/ml
„Tricor“ Dose: 145 mg API
Volume: 205 Liter
or 1000 mL
Itraconazole Solubility in Water: 1 ng/ml
„Sporanox“ Dose: 100 mg API
Volume: 100 Liter
What can we do to dissolve these poorly-soluble drugs in the human body? The solution lies in solubility enhancement, performed via mixing API crystals with soluble carriers. With this method, dissolution, absorption, and therapeutic efficacy of drugs are increased.
Poorly-soluble drugs and Amorphous Solid Dispersion
The concept of solid dispersions originally derived from the investigation of generation and dissolution performance of eutectic melts of a sulfonamide drug and a water-soluble carrier in the early 1960s (Source: Sekiguchi K, Obi N. Studies on the absorption of eutectic mixtures. I.A. comparison of the behaviour of eutectic mixtures of sulphathiazole and that of ordinary sulphathiazole in man. Chemical and Pharmaceutical Bulletin. 1961;9:866–872. Link here). Solid dispersions represent a useful pharmaceutical technique for increasing the dissolution, absorption, and therapeutic efficacy of drugs in dosage forms. The term solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The most commonly used hydrophilic carriers for solid dispersions include polyvinylpyrrolidone (Povidone, PVP), polyethylene glycols (PEGs), Plasdone-S630.
(e.g. HPC, HPMCAS,
PVP, PVPA, PLGA PVA)
Crystalline API clusters
Amorphous API clusters
Screening methods for ASDs
Compare and see the difference.
There are various processing methods that are used for ASD formulations screening. Herein we consider physical mixture, solvent casting, hot-melt extrusion and VCM (Vacuum Compression Molding).
Physical mixture and solvent casting
Physical mixtures (the combination of two or more substances in which the identities are retained and are mixed in the form of solutions or suspensions) and solvent casting are largely used in pharmaceutical applications. With the solvent cast method, the API is either suspended or dissolved in a solution of polymers or any other ingredients dissolved in a volatile solvent, like water or ethanol. The advantages of this technology include uniform thickness distribution, optical purity and lossless preparation. The disadvantage of this technique is that either drugs or carriers, may decompose or evaporate during the fusion process at high temperatures. (Source: W. L. Chiou and S. Riegelman, “Pharmaceutical applications of solid dispersion systems,” Journal of Pharmaceutical Sciences, vol. 60, no. 9, pp. 1281–1302, 1971. Link here)
Hot-melt extrusion, which was originally used in plastic, food and metals, has gained a significant role in the 1970s and nowadays it's widely used in pharmaceutical applications and drug manufacturing (Source:
Melt Extrusion: Materials, Technology and Drug Product Design, edited by Michael A. Repka, Nigel Langley, James DiNunzio. Link here). Hot-melt extrusion allows preparing fast release solid dispersion dosage forms. The physical mixture of a drug and a water-soluble carrier is heated directly until they both melt. The melted mixture is then cooled and solidified rapidly in an ice bath with vigorous stirring. The final solid mass is then crushed, pulverized, and sieved, which can be compressed into tablets with the help of tabletting agents. (Source: W. L. Chiou and S. Riegelman, “Pharmaceutical applications of solid dispersion systems,” Journal of Pharmaceutical Sciences, vol. 60, no. 9, pp. 1281–1302, 1971).
Hot-melt extrusion (HME) is the most preferred and effective method for manufacturing amorphous solid dispersions at production scale. Still, the main disadvantage of this technique consists in consuming large amounts of samples when used for formulation development.
VCM: the innovative screening method for HME formulations
Fast and lossless sample preparation
MeltPrep VCM is the novel screening method which allows the preparation of thermoplastic dosage forms (e.g. ASDs or implants in the milligram to gram-scale). The great innovation of this technology consists of a totally lossless approach to melt material into a defined shape without air inclusions. VCM lossless approach is a powerful tool to speed up pharmaceutical formulation and process design.
How does VCM speed up drug formulation development?
There are various stages in drug formulation development. In drug discovery and pre-clinical stage of formulation, there are many compounds to deal with, and the costs are rather high, small scale extrusion methods are used in this phase, and around 5-10 gr of material is generally needed for every experiment. MeltPrep VCM Tool can make a crucial difference in this early formulation stage development as it works with few milligrams of API, significantly reducing material waste and so the costs related to it. Costs and amounts are generally reduced as we proceed to the next stages of formulation development. In the scale-up phase, we do offer ExtruVis as a valuable ally for troubleshooting of continuous processes. It allows easy Residence Time Distribution measurement in all the processes in which a visual trace can be applied.
VCM for in‐vitro Drug Dissolution Studies
Fast sample preparation to obtain the best results.
Controlled drug delivery systems are advantageous over conventional dosage forms as they yield more stable plasma profiles, allow for reduced administration frequency, and minimize the potential of side-effects. While conventional dosage forms release the drug within a comparatively short time frame, CDDSs contain polymers to control drug release and thereby, the onset and duration of the drug’s action in the body. Multilayer samples are requested in galenic to study drug diffusion and release. A well-known example of such a dosage form is the intra-vaginal birth control ring (IVR) from Merck (NuvaRing™).
Drug loaded core
e.g. Ø10 mm
IVR e.g. Ø 50 mm
Drug loaded core
VCM Technology enables the production of multilayer samples. Layers of different materials are prepared one by one and then stacked in the desired order and loaded into the VCM Tool. By performing an additional VCM cycle, they are fused to one solid multilayer sample
Multilayer Sample with distinct layers and sharp interface(s)
Pilot plants and six-digit Euro investments were required for prototyping of pharmaceutical dosage forms with melt-processed carriers in the past. Now, the VCM technology enables rapid prototyping at a fraction of costs and time required for traditional prototyping methods. VCM can be used for different applications: rheology, diffusion studies, DSC measurements, spectroscopy and many more.