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Sonocrystallization Proven Across Scale

1.

INTRODUCTION

The application of power ultrasound (20 100 kHz) to crystallization and chemical processing is an intensification technology that has undergone significant development over the past 15 years or so and has a significant future ahead. It has been known for 80 years that ultrasound can have interesting effects on chemical and biochemical systems as well as influencing events in crystallization but the absence of scale up equipment led to that intransigence. However, recent advances in equipment have made its implementation at industrial scale not only feasible but preferable over existing chemical processing methods. There is a lot of interest in the application of ultrasound to crystallization in the pharmaceutical and fine chemicals sectors of industry. Prosonix proprietary technology ranges from the laboratory scale TM SonoLab through to commercial scale Prosonitron Reactor, allowing the most cost effective production of API with controlled morphology, particle size distribution, polymorphism, and minimal residual solvent levels. Tests have shown that other vendors are not able to meet the exacting Pharmaceutical requirements from a mechanical robustness perspective, nor critically provide the level of intellectual property support that is required to ensure an appropriate level of freedom to operate, independent of the means of delivery of ultrasound. The Prosonitron Reactor Systems have been successfully tested by multiple Pharmaceutical companies worldwide and were chosen by Pfizer Manufacturing Group in Ringaskiddy Ireland for their New Product Launch Facility. This selection followed an extensive test program independently undertaken by Pfizer building on our relationship with their PR&D team in Sandwich. The technologies are focussed on the same design principals and importantly utilize transducer based technology which allows distribution of acoustic energy into a liquid very effectively by using a number of low-power transducers bonded to the outside of the flow cell and in the case of the Prosonitron a cylindrical duct. This avoids the problems of using high-powered probe based equipment where metal particles can be shed into the crystallizing liquor. Typical equipment for pharmaceutical development through to manufacture fabricated from Stainless Steel or Hastelloy is shown in Figure 1.

SonoLabTM SL10 Laboratory scale

SonoLabTM SL 250 Kilo Lab scale

5 L HD Prosonitron Commercial scale

Figure 1. Prosonix Technology utilized across scale

WHITE PAPER 2. SONOCRYSTALLIZATION

2.1

Key Benefits of Sonocrystallization


Control particle size, shape, crystallinity, polymorphism Eliminate problems associated with physical seeding Improve batch consistency, filtration, isolation and drying Improve formulation consistency, stability and performance Enhance dissolution of poorly soluble drugs Increase cGMP compliance

2.2

Theory

Sonocrystallization utilises power ultrasound and resultant acoustic cavitation (Figure 2) to assist in nucleation of metastable solutions and subsequent crystal growth (Figure 3). The reasons why such local and transient energy concentrations assist with nucleation are difficult to explain but local dramatic temperature and pressure changes, shockwaves and rapid local cooling rates may all contribute to nucleation in the regions of the supersaturated solution or perhaps we can simply overcome the energy barriers associated with nucleation. Cavitation appears to be particularly effective as a means of inducing nucleation in a controlled and reproducible way and this provides a well-defined start point for the crystallization process. Sonocrystallization can also eliminate the requirement to add seed crystals, which can be particularly advantageous in contained pharmaceutical crystallization processes. Reduced acoustic power levels can lead to streaming effects rather than stable or violent transient cavitation, which can be useful to help crystal growth.

Figure 2. Ultrasonic Mechanical Vibration activating Transient Cavitation in Solution

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Figure 3. Cavitation enabled clustering leading to Nucleation at Low/Least Supersaturation

In many respects, the ease or difficulty of carrying out a crystallization process can be linked to an understanding of the metastable zone (MZ). Typically the application of high-intensity 20 kHz ultrasound can lead to narrowing of the metastable zone width (MZW) as shown in Figure 4. This MZW narrowing can range from a few degrees to twenty or more when crystallizing sugars. By narrowing the MZW 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. The optimum needs to be determined by experimental investigation. It 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, proteins and polymorphic systems.

Figure 4. Ultrasonic Narrowing of Metastable Zone Width

Where a crystallization is insonated continuously throughout its cooling period, large numbers of very small crystals can be formed. The small crystal size arises because the induced nucleation continues throughout the duration of the process, at the expense of the slower growth processes as can be seen

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in Figure 5. It is possible that ultrasound may also induce secondary nucleation by mechanically disrupting crystals that have already formed.

Figure 5. Enhanced Nucleation and Uniformity by Sonocrystallization

It is possible to tailor a particle size distribution by using a short burst of ultrasound to nucleate large crystals, and the production of small crystals via continuous insonation. There are various ways in which this may be carried out, for example by using pulsed ultrasound, or application in intermittent bursts, and the optimum usually needs to be determined by trial and error. We have tailored a number of commercial products to a size specification in this way. In crystallizations induced by the addition of an antisolvent, where high supersaturations may be produced very rapidly, we have shown that the application of ultrasound not only reduces the induction times of nucleation, but also the spread of induction times at a given level of supersaturation and leads to a more unimodal and importantly tighter particle size distribution. The ultrasonic induction of crystal nucleation invites comparison with seeding. Seeded crystallizations are very common in the isolation of pharmaceutical actives, but they usually require operator intervention to add the seeds, which may entail designing a complicated engineering arrangement to control the seed addition while maintaining containment. In a batch process, seeds have to be added at precisely the correct time during the development of the supersaturation profile. Addition too soon to a solution that is undersaturated will result in the seeds dissolving. Seeding too late will also be ineffective because the solute material may already have crashed out of solution, giving a product of inferior physical characteristics. Ultrasonic seeding offers all the advantages of conventional seeding without many of the drawbacks. The exact point of nucleation can be tightly controlled, as well as the number of nuclei generated. The application of ultrasound to nucleate contained and sterile processes in place of seeding has been a potential niche application, since many of the difficulties of seeding in such environments may be avoided. Sterile solutions are often difficult to crystallize in any case, because the conditions exclude a significant fraction of the minute particulate material that brings about heterogeneous primary nucleation in conventional crystallizations. Ultrasonic equipment can be easily engineered into process plant, and the application of ultrasound can be started and stopped at the flick of a switch. If the ultrasound is applied too early at undersaturation, there will be no effect (except possibly slight heating of the solution), and a further burst may be applied subsequently at the correct stage of the process.

WHITE PAPER 3. SCALE-UP AND EQUIPMENT DEVELOPMENT

An attractive feature of Prosonix Prosonitron and Sonocrystallization technology is that it can be applied at any stage in a product pipeline. This scale-out feature of the technology ensures that success in the lab can be replicated across scale. The in-line continuous flow or batch mode process can be applied to intermediates, excipients, APIs, binders and sugars, and importantly can be validated across scale in cGMP environments. Figure 6 represents the various devices across scale and one of the key principals Specific Power Input that needs to be carefully controlled on scale up. The Key Prosonitron design benefits are as follows: Ease of maintaining specific power input to the process liquid and surface intensity at all scales Ability to reproduce flow regime and residence time by configuration choice Result is a system that can deliver consistent processing throughout scale-up from pilot to production Key Process and Engineering Parameters 1. Batch Specific Power Input 2. Batch Specific Energy Input 3. 4. Surface Intensity Residence Time

5. Temperature 6. Physical properties of solutions Other factors also important to the scale up process but less critical include the number of passes through the cell and how the ultrasonic energy is dosed, the specific energy input per pass, the field intensity and the Reynolds number.

Figure 6. Effective Energy Scale Up through maintaining core Technology design principals

WHITE PAPER 4. TECHNOLOGY 4.1 SonoLabTM SL10 Laboratory Application

Figure 7. The SonoLab


TM

TM

SL10 coupled to the Syrris Atlas

TM

Platform
TM

Utilising the new SonoLab equipment in conjunction with the Syrris Atlas platform now provides customers a sound basis for quality ultrasonic experimentation and a seamless transition from TM laboratory to pilot plant and beyond. The scale of the SonoLab SL10 is ideally suited for batch operation of 100 ml up to 10L. Operators can be safe in the knowledge that laboratory results can be TM successfully implemented at kilo scale using the SonoLab SL250 and at commercial scale using the Prosonitron systems. Uniquely, SonoLab incorporates the same bonded transducer based design that is featured in the operation of Prosonix larger scale Prosonitron reactors. Prosonix now have a Worldwide marketing partnership with Syrris Ltd. (UK) which positions Syrris as TM the prime channel to market for Prosonix new SonoLab SL10 laboratory scale sonocrystallization and sonoprocessing equipment.
TM

4.2

SonolabTM SL250 KiloLab Application


TM

The SonoLab SL250 bridges the gap between Laboratory and Commercial application of the technology and is a key device for proving true scale up in a Kilo Lab environment. The SL250 is directly designed based upon the Prosonitron reactor technology and is capable of operating with volumes of between 10L to 100L in recirculation.

Figure 8. The SonoLab

TM

SL250 in recirculation with different sized glass vessels at Kilo Lab Scale

WHITE PAPER 4.3 Prosonitron- Commercial Application

One of the most important barriers to the adoption of power ultrasound technology in manufacturing has been the lack of suitable equipment for use in industrial environments at the scale required particularly where flammable solvents are in use. Most discoveries in sonochemistry and sonoprocessing have been carried out in laboratories on the mg g scale using either high-intensity probe or bath systems. There is a fundamental requirement for equipment that may be operated simply and reliably at the kg multi-tonne scale in the manufacturing of fine chemicals and pharmaceuticals and importantly in an explosion proof environment.

Figure 9. Commercial applications (Left Recirculation) (Right Continuous)

The Prosonitron technology designed and manufactured by Prosonix for Sonocrystallization and Sonoprocessing avoids resonance, standing waves and coherent wave relationships. There are a number of advantages in using non-coherent ultrasound: The more even distribution of the ultrasound through the working fluid is a key benefit. In addition one can design equipment with greater flexibility in terms of dimensions, frequency and configuration. Prosonix embarked on non-coherent designs after early experience with multi-transducer systems gave rise to difficulties with transducers tuning in to each other and of mechanical resonance in system components. Such difficulties can undoubtedly be more easily overcome with modern transducers and system designs. The original multi-transducer designs, were based on a 4 5 L insonated volume as a cylindrical duct 120 mm in diameter, fitted with three radially mounted transducers. To reduce surface erosion and mechanical stresses at the point of contact, a liquid barrier was employed between the transducer and the (thinned) duct wall. This unit was designed for non-coherent ultrasonic operation with a nominal frequency of 20 kHz. Experience of operating the unit showed that the three transducers tuned to slightly different frequencies between 19 and 21 kHz, and spot tests with aluminium foils and hydrophones indicated that the power input densities were reasonably uniform throughout the 4 5 L working volume. The technology employs direct bonding of the transducer to the surface of the vessel utilizing transducers with low individual outputs. The Prosonitron system has been designed in order to capacitate a large number of transducers to give an acoustic pattern that is completely uniform and non-coherent above the cavitational threshold throughout the working volume. The use of low-output transducers gives the additional advantage of avoiding the phenomenon of cavitational blocking (acoustic decoupling), which arises where power densities close to the delivery point are very high. In addition these multi-transducer units very effectively concentrate ultrasonic intensity towards the central axis of the cylinder and away from the vessel walls, thus reducing problems of erosion and particle shedding. This vessel can be operated in batch mode or for larger scale work, in continuous mode whereby units can be combined in a modular fashion for scale-out and increased residence -2 time. In summary, a plurality of low electrical and acoustic power (~1-3 Wcm ) transducers produces

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25 150 WL , but ideally 40 80 WL . The power can be applied continuously or pulsed. A typical examples of the flow-cell are shown in Figures 9,10 and 11 .

Figure 10. Sound Waves travel radially inward building in intensity to focus cavitation at the centre of the cell away from the walls (Left NPL Acoustic Mapping) (Right CAD drawing of focussed energy)

The Prosonitron can be manufactured either from hastelloy or 316 stainless steel. For Pharmaceutical application it is designed and manufactured to explosion-proof ATEX certification (for use with flammable solvents in a zoned process area). Scaling out the fundamental flow-cell design in one dimension facilitated the design and manufacture of the 1.2 m flow-cell used in the bulk scale alumina production at Aughinish Alumina in Ireland and Alcoa- San Ciprian in Spain (Figure 9 right).

Figure 11. The Prosonitron Scale Out Feature allows for Limitless Scale Up Capability

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5.

ROBUSTNESS AND EFFICIENCY OF TECHNOLOGY

Prosonix has taken great care to evaluate through extensive testing the robustness of the technology with respect to alternative methods of delivering ultrasound. It has been shown and is widely recognised by the Scientific community that probe based devices are inefficient and not scalable. The reason for this is because they are inherently high power devices emitting high energy over small surface areas which can lead to acoustic decoupling at the emitting face and subsequently metal shedding of equipment. This of course is completely unacceptable for the manufacture of Pharmaceutical products. Other technologies include Magnetostrictive devices which emit so much energy that not only has there been cause for concern with flammable solvents in flash ignition they also are known to shed metal to a high degree. Figure 12 illustrates this quite simply.

Figure 12. Spreading of Ultrasonic input over the whole surface of the cell allows significant specific power input to the fluid without demanding high surface intensity (conversely to probe technology)

It is very important in Sonocrystallization and also in Sonomilling to understand that more power does not mean more effect. Prosonix have worked across a very wide range of Pharmaceutical small molecules for Sonocrystallization and Sonoprocessing and can confirm that in many instances less power and more subtle delivery of power is often more effective. Generally utilizing low energy but focusing it efficiently is key to successful delivery of ultrasound in order to efficiently cavitate a solution media. Figure 13. illustrates the ideal operating range for the Prosonitron Technology for Sononucleation, Sonomilling and Ultrasonic Particle Rounding. The Prosonitron successfully combines low surface intensity to avoid surface erosion, moderate power input focused into the heart of the process liquid to avoid over processing and residence time of several seconds to allow time for process kinetics, heat transfer and mixing to keep pace. In addition to this there are no internal moving parts and easy clean polished surfaces allow for ease of use in a manufacturing environment.

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Figure 13. Prosonitron Operating Range

6.

CONCLUSION

Prosonix proprietary technologies are designed solely with the Pharmaceutical Customer in mind. They are engineered for purpose to deliver significantly added value solutions and have been proven across scale with multiple customers worldwide, time and time again. Contact us today, to understand how Prosonix can transform the economics and robustness of your crystallization process, and deliver best in class drug product performance. Christian Jones Business Development Manager, Prosonix Ltd. Tel: +44 (0) 1865 784 240 Mob: +44 (0) 7968 707 284 christian.jones@prosonix.co.uk www.prosonix.co.uk

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