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!

Poorly-soluble API

e.g. Indometacin

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Carriers

PVA

PVP

PCL-PVAc-PEG

PMMA

Transparent VCM Discs

Transparent extrudates

VCM

mg-to-g scale & no material loss

Hot-melt extrusion

>g scale & high material loss

Solubility of Active Pharmaceutical Ingredients

The basics.

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

  Abbvie

Volume: 205 Liter

Dissolution Test

Standard
Volumes

500, 900,

or 1000 mL

Itraconazole Solubility in Water:   1 ng/ml

  „Sporanox“ Dose:   100 mg API

  Janssen-Cilag

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

Solubility enhancement. 

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. 

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Lattice Energy
limits solubility

Manufacturing

Amorphous carrier

(e.g. HPC, HPMCAS,
PVP, PVPA, PLGA PVA)

API Crystals

Crystalline API clusters

Amorphous API clusters

Glassy solution

Molecular dispersion

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

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

Diffusion barrier

100  μg

4 mm

Diffusion barrier

100  μg

e.g. Ø10 mm

Lateral surface

sealed with

barrier glue

Cross

section

IVR e.g. Ø 50 mm

Drug loaded core

Diffusion barrier

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.

Compare VCM and HME in ASD formulation screening 

Learn from the direct experience.

A recent publication investigated the processability of VCM for the creation of amorphous formulations and to compare its results with Hot-melt extruded-processed formulations. Mixtures of indomethacin (IND) with drug carriers (Parteck® MXP, Soluplus®, Kollidon® VA 64, Eudragit® EPO) were processed using VCM and extrusion technology. Click on the button below to learn how VCM is a helpful tool to save valuable material in your lab and speed up your drug formulation development.

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