Increased Bioavailability Using New Formulation Technology

Professor Anant Paradkar holds an Interdisciplinary Chair in Pharmaceutical Engineering Science and is Director of the Centre for Pharmaceutical Engineering Science (CPES), University of Bradford. He completed his PhD in Pharmaceutics from Nagpur University and joined Bradford following a 20-year academic career in India. He has worked on various interdisciplinary collaborative research projects in the areas of product and process development. Paradkar has a strong background in crystal and particle engineering. Major crystallisation technologies being developed at his laboratory include HME, spherical crystallisation, microwave and ultrasound assisted processing. Paradkar has received Research and Knowledge Transfer grants totalling more than £1 million pounds from agencies including the Engineering and Physical Sciences Research Council (EPSRC), the Technology Strategy Board (TSB) and small and big pharma companies. He has been awarded a Yorkshire Enterprise Fellowship to strengthen exploitation and impact of his research work. To date, Paradkar has supervised 15 PhD and 50 MPharm candidates and published over 100 research papers.

Since its formation in April 2010, a key focus of the Centre for Pharmaceutical Engineering Science (CPES) has been novel green technologies for pharmaceutical and biopharmaceutical processing. Examples of these technologies include hot melt extrusion (HME), spray drying, ultrasound, injection moulding, milling and microwave assisted synthesis. The CPES has a significant interest in improving the physicochemical properties of poorly soluble drugs by using the aforementioned green technologies.

Background: The model that has brought Hot Melt Extrusion innovation to life

The CPES is an interdisciplinary research centre at the University of Bradford, UK. The University’s engineering laboratories have over 20 years of experience in polymer and reactive extrusion. Indeed, CPES covers the pharmaceutical sciences and polymer and process engineering disciplines with expertise in pharmaceutical materials, drug delivery systems, process development, material characterisation and process analytical technology (PAT).

The state-of-the-art pharmaceutical extrusion laboratories at CPES are located within the Interdisciplinary Research Centre (IRC) in Polymer Engineering. CPES also has pharmaceutical formulation laboratories within the School of Pharmacy and access to characterisation facilities run by the University’s Analytical Centre.

The University of Bradford partners with companies such as Aesica Pharmaceuticals to meet the full expectations and needs of the market when utilising innovation like HME in pharmaceutical formulation, namely a complete solution from bench-scale work at the CPES to generating clinical trial and commercial products at Aesica Pharmaceuticals’s cGMP site in Nottingham, UK.

Funded research projects at the CPES fall into two categories: industrial cooperation and core scientific. Industrial cooperation projects include partnerships such as the one with Aesica Pharmaceuticals while the core scientific ones focus on research that may be relevant to future industry partners and allow the centre to build up a solid scientific base. Knowledge transfer partnerships with relevant companies also aid technological innovation. 

Hot melt extrusion — innovation in processing technology

A key focus of the Centre is to understand the process of HME and explore its novel pharmaceutical applications. Extrusion is a process that involves forcing raw material or a mixture through a die or orifice under set conditions such as temperature, pressure, rate of mixing and feed rate for the purpose of producing a stable product of uniform composition.

HME is one of the most commonly used processing technologies in the plastic, polymer, rubber and food industries. The pharmaceutical industry has shown an increased interest in HME due to the many advantages it has over conventional technologies. This technology has been shown to be extremely robust and a viable method of producing various drug delivery systems such as tablets, capsules, pellets, films and implants.

Extrusion involves one or two co-rotating screws that convey material along an enclosed barrel and consists of three main parts: an opening through which material is fed, the barrel and the die. A variety of extruders are utilised at the Centre, including a Thermo Scientific HAAKE MiniLab (5–10 gm) micro compounder and 16 mm co-rotating twin screw extruder.

The CPES has expertise in pharmaceutical product development through its links with the School of Pharmacy at the University of Bradford. Major targets in product development include:

• poorly soluble drugs: solid dispersions, co-crystals and polymorphs

• controlled release systems

• moulded products: tablets and implants

• transdermal drug delivery technologies and mucoadhesive films

• inhaled drug delivery systems

• novel drug delivery systems to address needs of elderly care.

At present, nearly 40% of the new chemical entities (NCEs) being discovered have poor water solubility (Biopharmaceutics Classification System (BCS) Class 2 and 4, with particular emphasis on Class 2). This is a serious drawback for drug formulation and as a consequence, many new potential drugs fail in the formulation stages. More than 80% of drugs are marketed as solid formulations and 90% of them are crystalline in nature. Active Pharmaceutical Ingredients (APIs) can exist in various solid forms, such as polymorphs, pseudopolymorphs (solvates and hydrates), salts, co-crystals and amorphous solids. Each form may possess its own unique mechanical, thermal, physical and chemical properties that can have a significant effect on the solubility, bioavailability, hygroscopicity, melting point, stability, compressibility and other performance characteristics of the drug.

HME has been applied in the pharmaceutical industry for preparing solid dispersions to improve the solubility of poor water soluble drugs. Solid dispersions prepared by HME can exhibit controlled drug release and provide improvements in dissolution. The CPES has developed mini tablets that have fast dissolution rates for a small dose drug using HME technology. This technology avoids the many unit operations encountered in conventional tablet processing and can be easily scaled-up for mass manufacturing purposes. Differential scanning calorimetry (DSC), shear cell, rotational rheometer, capillary rheometer and hot stage microscopy are used as screening techniques by the CPES to optimise HME processing.  

In recent years, another alternative to polymorphs and salts has emerged in the form of pharmaceutical co-crystals. Pharmaceutical co-crystals have two components: an API and a co-former. The API is usually selected because of its poor solubility, and it is matched with a co-former to improve its solubility. To synthesise a pharmaceutical co-crystal, one has to select an API and co-former that can potentially form hydrogen bonds with each other. Once chosen, there are several methods that can be used for their synthesis, however at the CPES, HME is the preferred choice.

The CPES was successful in obtaining a £500k research grant from the Engineering and Physical Sciences  Research Council (EPSRC) in March 2012, to explore the underpinning science behind the formation of co-crystals in this innovative process. The findings of this project will significantly improve the potential for use of co-crystals in commercial drug delivery. Understanding the fundamental mechanisms behind co-crystal formation and the subsequent optimisation of this process will accelerate industrial interest in this field, providing direct benefits to the UK pharmaceutical sector and wider long-term benefits to public health through the availability of otherwise unusable drugs.

Using HME, the API and co-former are usually fed into the extruder in a 1:1 or 2:1 ratio, depending on the specific co-crystal to be made. Parameters such as temperature, residence time and shear are critical during this process because it is thought that the mixture must undergo good mixing and be allowed to partially melt to allow co-crystals to form. Studies carried out by the students at the CPES have adjusted the parameters to achieve a good co-crystal yield for several different API-co-former systems. The CPES has successfully generated ibuprofen-nicotinamide, carbamazepine-nicotinamide, caffeine-malic acid, salicylic acid-nicotinamide and itraconazole-malic acid co-crystals using HME.

Rheological studies are also underway in the department to help understand the effect of shear force on polymorph and co-crystal formation. This is an important study because the mixing intensity and shear can be changed when designing the screws used for HME. The screw configuration can have a significant effect on the co-crystal yield achieved and it is thought that shear force plays a vital role.

A polymorph is a solid crystalline phase of a given compound resulting from the possibility of at least two different arrangements of the molecules of that compound in the solid form. The CPES has patented a solvent-free technology to generate and stabilise metastable polymorphs without the need of any additional stabilisers (patent application number: GB 1208489.3). This method involves processing the marketed available form of artemisinin in a hot screw extruder at a temperature below the melting point of the drug; the resultant product is a more soluble form of artemisinin.

Artemisinin can exist in two structural forms: orthorhombic and triclinic. The orthorhombic form is the most stable and is the only form available on the market while the triclinic form possesses good water solubility and has shown four times better bioavailability compared with the marketed form. The reported methods of preparing the triclinic crystal include crystallisation involving a solvent and the addition of an anti-solvent. However, the triclinic form obtained is metastable and undergoes solvent mediated transformation to the original form. Data suggests that minor traces of solvent (1.25%) may favour solvent mediated transformation and are responsible for the formation of the other form. This is a simple, continuous, solvent-free, reproducible, scalable process, with high purity and stability compared with conventional techniques. Moreover, the product obtained is in an agglomerated form that reduces several unit operations in downstream processing.

The inventive process under consideration utilises the application of appropriate shear and temperature in combination by processing the material within a heated, screw-driven process, which leads to polymorphic transformation. The formation of the triclinic form is confirmed by comparing powder x-ray diffraction (PXRD) patterns of the extruded samples with reference patterns obtained from the Cambridge crystallographic database. Being solvent-free, the instability associated with the residual solvent is avoided. The prepared triclinic form of artemisinin showed a two-fold increase in bioavailability compared with the orthorhombic form. This method is not only specific to artemisinin but can be applied to many other pharmaceuticals.

The FDA now encourages process innovation in the pharmaceutical industry through better process understanding, which is achieved by adopting quality by design (QbD) and process analytical technology (PAT). PAT allows researchers at the CPES to understand the HME process in more detail. Near-infrared spectroscopy (NIRS) and Raman spectroscopy can be used as in-line tools for monitoring polymorph/co-crystal formation during hot melt extrusion via high temperature, fibre-optic probes. The probes can be situated at different positions along the extruder barrel for quantitative analysis of the material during extrusion. Calculated purity from off-line powder X-ray diffraction is used to calibrate the in-line NIR and Raman measurements. PAT provides an accurate view of the processes happening during extrusion and can help locate the point at which polymorph crystals or co-crystals are formed along the barrel. In the future, this PAT method could be used as a HME quality control system.

The CPES has a good infrastructure and special expertise in the area of in-line process monitoring of pharmaceutical extrusion and other processes utilising:

• infra-red spectroscopy

• raman spectroscopy

• rheology

• ultrasound.

It also provides expertise in the areas of:

• rheological characterisation for process optimisation

• real-time monitoring of biopharmaceutical aggregation

• monitoring of molecular assembly.

The CPES welcomes new opportunities to develop partnerships and extend its network.

For more information, contact Dr. Riddhi Shukla, Business Development Manager, the CPES, University of Bradford, +44 1274 235571, r.y.shukla@bradford.ac.uk, www.pharmaceutical-engineering.brad.ac.uk.