ABSTRACT
In a previous study, a small-scale dynamic filtration device (SFD) was analyzed and the basic mechanisms governing the filtration process were characterized. The present work aims at improving the device's performance in terms of actual production. Various operation modes were tested in order to increase permeate flow and concentration factors (CF), while maintaining a fully continuous production mode. Both, a vacuum-enhanced and a pulsating operation mode, proved to be superior to the currently implemented open-operation mode. For example, for lactose, an increase of the CF could be achieved from 1.7 in open mode to 7.6 in pulsating operation mode. The investigated operation strategy enables process control systems to rapidly react to fluctuating feeds that may occur due to changes in upstream manufacturing steps. As a result, not only filtration performance in terms of permeate rate but also process flexibility can be significantly increased. Overall, vacuum-enhanced operation was shown to be most promising for integration into an industrial environment. The option to elevate achievable concentration factors, ease of flow monitoring as well as the ability to react to changes in the feed conditions allow for effective and efficient continuous small-scale filtration.
Subject(s)
Filtration/methods , Pharmaceutical Preparations/chemistry , Technology, Pharmaceutical/methods , Lactose/chemistryABSTRACT
Over the last years, continuous manufacturing has created significant interest in the pharmaceutical industry. Continuous filtration at low flow rates and high solid loadings poses, however, a significant challenge. A commercially available, continuously operating, dynamic cross-flow filtration device (CFF) is tested and characterized. It is shown that the CFF is a highly suitable technology for continuous filtration. For all tested model active pharmaceutical ingredients, a material-specific strictly linear relationship between feed and permeate rate is identified. Moreover, for each tested substance, a constant concentration factor is reached. A one-parameter model based on a linear equation is suitable to fully describe the CFF filtration performance. This rather unexpected finding and the concentration polarization layer buildup is analyzed and a basic model to describe the observed filtration behavior is developed.
Subject(s)
Filtration/methods , Suspensions/chemistry , Algorithms , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Desiccation , Drug Compounding , Ibuprofen/administration & dosage , Ibuprofen/chemistry , Linear Models , Membranes, Artificial , Models, Theoretical , Particle Size , ViscosityABSTRACT
We present an in situ hydrophobic salt forming technique for the encapsulation of weakly hydrophobic, ionizable active pharmaceutical ingredients (API) into stable nanocarriers (NCs) formed via a rapid precipitation process. Traditionally, NC formation via rapid precipitation has been difficult with APIs in this class because their intermediate solubility makes achieving high supersaturation difficult during the precipitation process and the intermediate solubility causes rapid Ostwald ripening or recrystallization after precipitation. By forming a hydrophobic salt in situ, the API solubility and crystallinity can be tuned to allow for NC formation. Unlike covalent API modification, the hydrophobic salt formation modifies properties via ionic interactions, thus circumventing the need for full FDA reapproval. This technique greatly expands the types of APIs that can be successfully encapsulated in NC form. Three model APIs were investigated and successfully incorporated into NCs by forming salts with hydrophobic counterions: cinnarizine, an antihistamine, clozapine, an antipsychotic, and α-lipoic acid, a common food supplement. We focus on cinnarizine to develop the rules for the in situ nanoprecipitation of salt NCs. These rules include the pK(a)s and solubilities of the API and counterion, the effect of the salt former-to-API ratio on particle stability and encapsulation efficiency, and the control of NC size. Finally, we present results on the release rates of these ion pair APIs from the NCs.
Subject(s)
Drug Carriers/chemistry , Nanoparticles/chemistry , Polymers/chemistry , Chemical Precipitation , Cinnarizine/chemistry , Clozapine/chemistry , Drug Stability , Hydrogen-Ion Concentration , Hydrophobic and Hydrophilic Interactions , Ions/chemistry , Naphthols/chemistry , Particle Size , Salts/chemistry , Solubility , Thioctic Acid/chemistryABSTRACT
Growth kinetics of alpha L-glutamic acid was determined based on seeded batch desupersaturation experiments. The growth rate correlation applied in this study accurately describes the growth process in a temperature range of 25-45 degrees C and in a supersaturation range of 1-3. The newly developed approach for the growth rate characterization has the advantage of a high robustness especially with respect to the influence of competing particle formation mechanisms as nucleation or agglomeration. The efficient technique employs in situ process analytical technologies, e.g. attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) and focused beam reflectance measurement (FBRM), different ex situ analytical tools and population balance modeling combined with a non-linear least squares optimization algorithm to determine the growth kinetics. The growth mechanism was identified to be integration controlled and of birth and spread (B + S) type. The quality of the determined growth rate correlation was assessed by comparison with the experimental data and with literature data.
