Press Room

Article / Sep 19, 2003

Particle Design, New Technologies for Better Crystals

CPhI 2003, 19 September 2003

Hovione for CPhI 2003

The service of an API manufacturer not only involves the development of the chemical process and the supply of high quality API, when and where required, but also paying close attention to those physical parameters which make up the necessary requisites for a successful formulation. Chemical skills must be complemented by a pharmaceutical culture. For a successful custom synthesis partnership it is imperative that the API contractor be both cognizant of the importance of having the correct particle size and morphology, and be able to develop a process that delivers consistently the required crystal form and size. This is key in many galenic forms; in the field of inhalation for instance it is absolutely critical; it can also be the source of many last-minute surprises and frustrations until the matter is well controlled.

Traditional know-how includes: expertise in controlled crystallisation, micronization and jet milling. These are skills that Hovione has used for decades in its plants to achieve the desired crystal form and consistent particle size. All of this needs to be backed up with analytical techniques, including laser diffractometry and impaction, used in a manufacturing scenario, to assure the necessary QC controls.

But technology moves on….

Hovione is pleased to announce it is installing a state of the art Spray Drying facility, capable of evaporating 35 to 90 Kg of water per hour under the most stringent cGMP conditions. The supplier of the Spray Drier, Niro A/S has designed this to the most advanced specifications. It is equipped with two atomizer systems (a rotary and co-current two-fluid nozzle) to deliver injectable grade APIs and is configured to be “cleaned-in-place” it discharges into a classified clean-room. This multipurpose unit was the result of a close collaboration with Niro and allows Hovione to produce dry solids in either powder, granulate or agglomerate form from liquid feedstocks such as solutions, emulsions and pumpable suspensions. This technology will enable continuous production, at low-cost and with a high degree of precision, over a wide range of particle sizes. The system meets explosion-proof requirements and can therefore spray-dry out of most organic solvents in a safe and compliant environment. Niro has described the unit as one of the most flexible and versatile GMP compliant spray-driers that they have ever built.

Continuing its programme to expand scientific know-how in advanced technologies, Hovione is actively developing expertise in other particle design techniques: Supercritical Crystallization and Sono-crystallization.

Supercritical crystallization offers a trouble-free separation of the product from the solvent and the capability to control the size and form of the crystals. The principle is based on replacing a conventional solvent with a supercritical fluid, which may act as a solvent or as an anti-solvent. This technique may be used to produce very small particles with narrow size distribution.

Sono-crystallization uses ultrasound to influence crystallization behaviour by promoting cavitations within the liquid media, which serve as nuclei for new crystals to form. Benefits can include improved crystal habit, purity and the ability to manipulate crystal-size distribution and powder flow characteristics. It also offers a useful and more controllable alternative to seeding.

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Continuous Tableting (CT) is defined as continuous manufacturing of oral dose drugs, specifically tablets. As per ICH's Q13 definition1, a continuous manufacturing process in the pharmaceutical industry comprises at least two unit operations integrated from a mechanical and software perspective. There is a wide combination of possible CT process configurations that are dependent on the needs of the intended product formulation and each of the individual unit operations that constitute the process train can be continuous, semi-continuous, or batch processes. The typical manufacturing processes for tablet formulation are direct compression (DC), dry granulation (DG) and wet granulation (WG)2 - details on these manufacturing processes are beyond the scope of this article, so the interested reader is directed to relevant literature. The actual implementation of CT technology in a facility can broadly vary depending on the level of desired integration and automation. Process trains can be designed to be flexible and converted between multiple configurations (e.g. continuous DC, DG and WG), controlled by the end user from one single software and within a single clean room. The other possibility would be for subsections of the CT process to be divided into multiple clean rooms where inprocess materials are transferred between suites via a bin-to-bin approach (e.g. a granulation suite to prepare granules from raw materials followed by continuous DC (CDC) to blend the granules and produce tablets). The level of automation and instrumentation designed into the CT process (typically involving Process Analytical Technologies, PAT) can open the possibility to implement sophisticated control strategies. Key components of a control strategy that need to be considered for CT are material tracking and genealogy, knowledge of the residence time distribution (RTD), and in-process controls (spectroscopic and/or soft sensors based on process parameters). Holistically, these control strategy elements enable the implementation of a material diversion strategy to automatically divert out of specification material from the process. In their most advanced form, control strategies may also enable real time release testing (RTRt) of the final tablet drug product and reduce the off-line analytical burden and the number of operators needed to manage the process.   Read the full article at gmp-journal.com  

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