BackgroundLack of accounting for proton uptake and secretion has confounded interpretation of the stoichiometry of photosynthetic growth of algae. This is also problematic for achieving growth of microalgae to high cell concentrations which is necessary to improve productivity and the economic feasibility of commercial-scale chemical production systems. Since microalgae are capable of consuming both nitrate and ammonium, this represents an opportunity to balance culture pH based on a nitrogen feeding strategy that does not utilize gas-phase CO2 buffering. Stoichiometry suggests that approximately 36 weight%N-NH4+ (balance nitrogen as NO3-) would minimize the proton imbalance and permit high-density photoautotrophic growth as it does in higher plant tissue culture. However, algal media almost exclusively utilize nitrate, and ammonium is often viewed as ‘toxic’ to algae.ResultsThe microalgae Chlorella vulgaris and Chlamydomonas reinhardtii exclusively utilize ammonium when both ammonium and nitrate are provided during growth on excess CO2. The resulting proton imbalance from preferential ammonium utilization causes the pH to drop too low to sustain further growth when ammonium was only 9% of the total nitrogen (0.027 gN-NH4+/L). However, providing smaller amounts of ammonium sequentially in the presence of nitrate maintained the pH of a Chlorella vulgaris culture for improved growth on 0.3 gN/L to 5 gDW/L under 5% CO2 gas-phase supplementation. Bioreactor pH dynamics are shown to be predictable based on simple nitrogen assimilation as long as there is sufficient CO2 availability.ConclusionsThis work provides both a media formulation and a feeding strategy with a focus on nitrogen metabolism and regulation to support high-density algal culture without buffering. The instability in culture pH that is observed in microalgal cultures in the absence of buffers can be overcome through alternating utilization of ammonium and nitrate. Despite the highly regulated array of nitrogen transporters, providing a nitrogen source with a balanced degree of reduction minimizes pH fluctuations. Understanding and accommodating the behavior of nitrogen utilization in microalgae is key to avoiding ‘culture crash’ and reliance on gas phase CO2 buffering, which becomes both ineffective and cost-prohibitive for commercial-scale algal culture.

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Personalized medicine strives to deliver the ‘right drug at the right dose’ by considering inter-person variability, one of the causes for therapeutic failure in specialized populations of patients. Physiologically-based Pharmacokinetic (PBPK) modeling is a key tool in the advancement of personalized medicine to evaluate complex clinical scenarios, making use of physiological information as well as physicochemical data to simulate various physiological states to predict the distribution of pharmacokinetic responses. The increased dependency on PBPK models to address regulatory questions is aligned with the ability of PBPK models to minimize ethical and technical difficulties associated with pharmacokinetic and toxicology experiments for special patient populations. Subpopulation modeling can be achieved through an iterative and integrative approach using an adopt, adapt, develop, assess, amend, and deliver [(AAD)2] methodology. PBPK modeling has two valuable applications in personalized medicine: (1) determining the importance of certain subpopulations within a distribution of pharmacokinetic responses for a given drug formulation and (2) establishing the formulation design space needed to attain a targeted drug plasma concentration profile. This review article focuses on model development for physiological differences associated with sex (male vs. female), age (pediatric vs. young adults vs. elderly), disease state (healthy vs. unhealthy), and temporal variation (influence of biological rhythms), connecting them to drug product formulation development within the Quality by Design framework. Although PBPK modeling has come a long way, there is still a lengthy road before it can be fully accepted by pharmacologists, clinicians, and the broader industry.

The increasing use of metal-containing catalysts in producing pharmaceutical intermediates and active pharmaceutical ingredients, in conjunction with requirements of low metal content in a drug substance, has motivated the development of efficient separations processes for metals removal. In this paper, fixed-bed adsorption, an attractive alternative to batch adsorption, was investigated using a reaction mixture from a Heck coupling. Adsorption isotherm determinations using three candidate adsorbents revealed that QuadraPure TU had the greatest affinity and identified the optimal adsorption temperature. The bed residence time was key in obtaining good adsorption efficiency in subsequent fixed-bed experiments. Methods for palladium detection by HPLC were developed to monitor adsorption column performance in quasi real-time. A preliminary design methodology was developed in which actual breakthrough time is estimated from the experimentally determined tradeoff between bed efficiency and residence time. Even at the realized 55% bed efficiency, fixed-bed adsorption requires less than one-fourth the adsorbent needed for a single-stage batch adsorption process.

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