Pharmaceutical manufacturing is committed to making crystals and particles (although some drug substances can be viscous oils) and then modifying their properties so as to turn them into structured products. Surprisingly 5% to 10% of manufactured formulations fail to meet specifications. Global growth in 2008 for the $600B pharmaceutical market is forecast at 5-6%. In turn, the drug delivery market is growing at 5% per year and stands around $60 B for advanced drug delivery -the US market alone is tipped to grow at more than 18% to exceed $76 B by 2014.

However the pharmaceutical industry – and its service providers - must make improvements in the primary and secondary manufacture of drug substances. The imperative is that the industry should not lag behind others such as electronics and semiconductors – even the potato chip and laundry soap makers as described in the Wall Street Journal in 2003! Sonocrystallization from Prosonix is a technology that meets many of the guidelines laid out by the FDA with respect to their quality by design (QbD) initiative, aimed at guiding (the ICH Q8 guidelines of 2004) the pharmaceutical industry to improved invention, development and commercialization of structured products using technologies that will result in superior product quality.

Due to the limitations of conventional crystallization techniques macroscopic particles for say tablets (10-200 micron) and mesoscopic particles for drug inhalation (1-5 micron) are often manufactured by some very primitive pharmaceutical technologies (‘top down’ destructive methods) such as milling; a ‘sledgehammer’ and energy inefficient technique to turn large, regular crystals into irregular smaller particles that can undergo morphological change and surface polymorph transformations leading to amorphicity and decreased stability.

The particles can also be highly charged which undermines the handling and flow characteristics in subsequent formulation. Prosonix State-of-the-art particle engineering will allow control of crystal characteristics while maintaining high throughput, low cost and industrial scalability. Emerging crystallization and particle engineering technologies are now being developed to assist in both drug development and manufacture. Sonocrystallization is an effective means of inducing crystal nucleation in a controlled and reproducible way and this provides a well-defined start point for the pharmaceutical crystallization process. This allows focus on controlling the crystal growth via the residence time in the crystallizer.

We have used this combined approach to influence crystal size distribution, assist in morphological control, elimination of impurities in the crystal and improve solid-liquid separation behaviour. Sononucleation can also eliminate the requirement to add seed crystals, which can be particularly advantageous in contained pharmaceutical crystallization processes. The ease or difficulty of carrying out a crystallization process can be linked to an understanding of the metastable zone (MZ). For a cooling crystallization, the Metastable Zone Width (MZW) can be described as the temperature drop below the solubility curve at which solid starts to separate spontaneously for a given supersaturation level and cooling rate (supersolubility limit.

Typically the application Prosonix technology can lead to narrowing of the metastable zone width (MZW) but without the problems of using seed crystals. This MZW narrowing (MZW is broken line - see image left) can range from a few degrees to twenty or more for pharmaceutical products. By narrowing the MZW to nucleate at the blue asterisk it is possible to “tailor” a crystal size distribution between the extreme cases of a short burst of ultrasound to nucleate at lower levels of supersaturation and allow growth to large crystals, and the production of small crystals via continuous (or perhaps a longer single burst) insonation throughout the duration of the process.

Is possible that ultrasound may also induce secondary nucleation by mechanically disrupting crystals or loosely bound agglomerates that have already formed. The overall technique lends itself extremely well to almost any crystallization process of valuable pharmaceuticals and proteins. One particular new pharmaceutical we have worked extensively on has been shown to exhibit troublesome behaviour in terms of crystal habit. When high levels of supersaturation are reached (at the red 'X' and broken line MZW above) in a standard cooling crystallization, high nucleation rates, along with poorly controlled crystallization, leads to the proliferation of a distinct needle polymorph leading to poorly stirred slurries and variable product bulk density.

By using ultrasound at much lower levels of supersaturation (the blue asterisk) the highly desired stable polymorph can be easily produced and managed. Polymorphism is common amongst organic materials and given that small-molecule drugs can be flexible and exhibit significant internal freedom, it is no surprise that such entities can exist as two or more crystalline phases with different packing in the crystal lattice. Isolation of the “wrong” polymorph brings substantial problems in pharmaceutical applications but by careful application of ultrasound to a crystallizing system at the right level of supersaturation the ground state polymorph (the most thermodynamically favoured and least soluble) or one near the ground state can be isolated.

Using sonocrystallization to produce the desired particle size and distribution can be extremely valuable in helping avoid secondary processing techniques such as milling. Why manufacture large crystals and then obliterate them with such a technique when you could produce smaller particles ready for tableting - or better still microcrystalline inhalable therapeutics - by using sonocrystallization? Partner with Prosonix today!