Prior investigations comparing radial¯ow Rushton impellers with axial¯ow hydrofoil impellers (Max¯o T and A315) were extended at the pilot scale. Six types of impellers (disk-style Rushton, Prochem Max¯o T hydrofoils of three diameters pumping downwards and A315 hydrofoils pumping upwards and downwards) were compared for qualitative differences in power number behavior with Reynolds' number, single versus double impeller power draw, gassed power reduction with aeration number and gas hold-up. Power measurements were obtained using watt transducers which, although limited in accuracy and prone to interferences, were able to provide useful qualitative monitoring results. Measurements were conducted using three model liquid systems: water, glycerol and Melojel (soluble starch). Apparent viscosities for actual Streptomyces cultivations were estimated using measured gassed power values and the experimental relationships obtained for gassed/ungassed power to aeration number and power number to Reynolds' number for the glycerol model system. Results con®rmed the lower power number and lower shear environment for hydrofoil impellers, yet suggested useful trends for various process parameters and process¯uids.List of symbols c constant relating average tank shear rate to impeller speed g gravitational acceleration, 9X807 m/s 2 g c gravitational acceleration conversion factor, 1 kg Á m/s 2 Á N k¯uid consistency index n power law index n I number of impellers p T pressure at tank top, mPa v S super®cial velocity of sparged air based on tank diameter, m/s D I impeller diameter (tip to tip), m D T fermenter vessel diameter, m H tank hold up based on dispersion volume H L height of liquid in tank excluding bottom dish, m H T total height of tank, m IS impeller shear, s À1 ITS impeller tip speed, pD I N, m/s K constant relating N A to P g aP 0 N impeller speed, s À1 N A aeration or¯ow number, QaND 3 I N Fr Froude number, N 2 D I ag N P Newton or power number, P 0 aqN 3 D 5 I N Re Reynolds' number for impeller, ND 2 I qal N We Weber number for impeller P exp gas expansion power, m 3 as P 0 ungassed power draw, kW P g gassed power draw, kW P L power loss, kW Q volumetric gas¯owrate, m 3 as S impeller spacing, m V L ungassed liquid volume of tank, m 3 V T total volume of tank, m 3 W width of tank baf¯es, cm q liquid density, g/cm 3 q g gas density, g/cm 3 l viscosity, MPa Á s l a apparent viscosity, MPa Á s c T average shear rate in stirred tank, s À1 c V average shear rate in viscometer, s À1 r surface tension, dynes/cm 1 Introduction Substantial research has been conducted at Merck Research Laboratories comparing radial¯ow Rushton impellers with axial¯ow Prochem Max¯o T and Lightnin A315 impellers [4, 10, 15±17]. The main characteristics of these impellers are summarized in Table 1. It has been well-demonstrated that Rushton turbines lose up to 70% of their power draw when aerated due to the formation of air ®lled ventilated cavities behind the blades [17]. In high viscosity broths, these air cavities become stabilized [18] alth...

It is critical to consistently achieve the desired crystal form for an active pharmaceutical ingredient (API) because crystal form may affect the compound's chemical stability, bioavailability, and pharmaceutical processing performance. The extent to which a crystallizing system is driven by growth vs nucleation is dependent upon the level of supersaturation, defined as the difference between solution concentration and solubility. We describe a method for the accurate measurement of real-time supersaturation, which enabled us to develop and optimize an API crystallization via a feedback-control loop based on concentration measurement with online FTIR. In this contribution we discuss a novel extension of the published work [Zhou, G. X.; et al. Cryst. Growth Des. 2006, 6, 892-898] which ensured robust isolation of the thermodynamically most stable crystal form of an API. The system of interest is a monotropic polymorphic system with overlapping metastable zones. In order to ensure exclusive isolation of the desired form within a reasonable cycle time, a three-pronged approach was appliedsmaximize seed surface area through the use of milled seed, run the crystallization at a high temperature to increase crystal growth rate, and perform the crystallization at a high level of supersaturation relative to the desired, more stable form while keeping the concentration below the equilibrium solubility of the less stable polymorph. By carefully selecting the seed loading, we were also able to dial-in the target particle size directly via a growth-dominated crystallization, thus eliminating the need for post-crystallization product milling. As a result, a robust, efficient, and reliable crystallization process has been achieved to ensure isolation of the desired polymorph at target particle size.

Radial¯ow Rushton impellers were compared qualitatively with axial¯ow hydrofoil impellers (Max¯o T and A315) at the pilot scale. Six types of impellers were compared for qualitative differences in mass transfer. Measurements were conducted using three model systems: water, glycerol and Melojel (soluble starch). Power measurements were obtained using watt transducers, which although limited in accuracy and prone to interferences, were able to provide useful qualitative monitoring results. While there was little effect of impeller type on mass transfer as measured by the rapid pressure increase technique, signi®cant qualitative differences were observed using the rapid temperature increase technique speci®cally for the Melojel and glycerol model systems. The Miller correlation, relating gassed-to-ungassed power, was used effectively to qualitatively evaluate the power drop upon gassing for both the model systems and a Streptomyces fermentation for the various impeller types.A high oxygen demand Streptomcyes fermentation then was conducted in fermenters possessing each type of impeller. Performance was not adequate with the A315 impellers pumping upwards and the small diameter Max¯o T impellers. Peak titers and pro®les of the estimated apparent broth viscosity varied depending upon the impeller type. Mass transfer rates generally declined with higher viscosities when other fermentation operating conditions where held constant. Overall, values for OUR, k L a, P g /V L and other calculated mass transfer and power input quantities for the A315 pumping upwards and undersized Max¯o T (D T /D I 2.3) impellers were at the lower end of the range obtained for the larger Max¯o T (D T /D I 1.8± 2.0) and A315 impellers pumping downwards. Rushton impellers generally behaved qualitatively similar to hydrofoil impellers based on these calculated quantities. List of symbolsa surface area per unit volume of bubbles, cm A1 g gravitational constant, m/s 2 k¯uid consistency index k L mass transfer coef®cient n power law index t m mixing time, s v b bulk velocity, m/s v s super®cial velocity of sparged air based on tank diameter, m/s A cross-sectional area of the tank, m 2 D I impeller diameter (tip to tip), m D T fermenter vessel diameter, m D oi diffusivity of oxygen in water (w), glycerol (g) andMelojel (m), cm 2 /s N impeller speed, s A1 N A aeration or¯ow number, Q/ND 3 I N Fr Froude number, N 2 /D I g N m Mixing number, 1/t m N N P Newton or power number, P 0 /(qN 3 D 5 I ) N Q generalized pumping number, Q P /ND 3 I N Re Reynold's number for impeller, ND 2 I q/l N Sc Schmidt number, l/qD oi P 0 ungassed power draw, kW P g gassed power draw, kW Q volumetric gas¯owrate, m 3 /s Q P volumetric pumping rate, v b A, m 3 /s V L ungassed liquid volume of tank, m 3 q liquid density, g/cm 3 l viscosity, mPa á s l a apparent viscosity, mPa á s c T average shear rate in stirred tank, s A1 r surface tension, dynes/cm 1 Introduction For aerobic fermentations, oxygen management is about 15±20% of all operating costs. Consequently, a modest impr...

An ambient loop USP puri®ed water system has been designed and implemented using carbon and ion exchange resin beds, ultraviolet light systems and polishing ®lters to produce water consistently meeting or exceeding all USP XXIII quality speci®cations for puri®ed water. The circulation system is constructed of PVDF plastic piping material installed in a continuous fullydrainable loop. The system was sized for a pilot scale fermentation/harvest process at the 1000 l cultivation scale. This system passed all installation and operational quali®cation testing as well as sixty days of continuous performance quali®cation testing before entering into an ongoing monitoring regimen. Excursions outside acceptable water quality parameters during this extensive monitoring regimen were minimal. Sanitization of the system, along with bed and ®lter changes at the time of sanitization, was conducted every 3 to 6 months to insure consistent water quality.