Introduction: Oral drug delivery is the most favored route of drug administration. However, poor oral bioavailability is one of the leading reasons for insufficient clinical efficacy. Improving oral absorption of drugs with low water solubility and/or low intestinal membrane permeability is an active field of research. Cocrystallization of drugs with appropriate coformers is a promising approach for enhancing oral bioavailability. Methods: In the present review, we have focused on recent advances that have been made in improving oral absorption through cocrystallization. The covered areas include supersaturation and its importance on oral absorption of cocrystals, permeability of cocrystals through membranes, drug-coformer pharmacokinetic (PK) interactions, conducting in vivo-in vitro correlations for cocrystals. Additionally, a discussion has been made on the integration of nanocrystal technology with supramolecular design. Marketed cocrystal products and PK studies in human subjects are also reported. Results: Considering supersaturation and consequent precipitation properties is necessary when evaluating dissolution and bioavailability of cocrystals. Appropriate excipients should be included to control precipitation kinetics and to capture solubility advantage of cocrystals. Beside to solubility, cocrystals may modify membrane permeability of drugs. Therefore, cocrystals can find applications in improving oral bioavailability of poorly permeable drugs. It has been shown that cocrystals may interrupt cellular integrity of cellular monolayers which can raise toxicity concerns. Some of coformers may interact with intestinal absorption of drugs through changing intestinal blood flow, metabolism and inhibiting efflux pumps. Therefore, caution should be taken into account when conducting bioavailability studies. Nanosized cocrystals have shown a high potential towards improving absorption of poorly soluble drugs. Conclusions: Cocrystals have found their way from the proof-of-principle stage to the clinic. Up to now, at least two cocrystal products have gained approval from regulatory bodies. However, there are remaining challenges on safety, predicting in vivo behavior and revealing real potential of cocrystals in the human.

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Phenylacetaldehyde dehydrogenase catalyzes the NAD+-dependent oxidation of phenylactealdehyde to phenylacetic acid in the styrene catabolic and detoxification pathway of Pseudomonas putida (S12). Here we report the structure and mechanistic properties of the N-termininally histidine-tagged enzyme, NPADH. The 2.83Å X-ray crystal structure is similar in fold to sheep liver cytosolic aldehyde dehydrogenase (ALDH1), but has unique set of intersubunit interactions and active site tunnel for substrate entrance. In solution, NPADH occurs as 227 kDa homotetramer. It follows a sequential reaction mechanism in which NAD+ serves as both the leading substrate and homotropic allosteric activator. In the absence of styrene monooxygenase reductase, which regenerates NAD+ from NADH in the first step of styrene catabolism, NPADH is inhibited by a ternary complex involving NADH, product, and phenylacetaldehyde, substrate. Each oligomerization domain of NPADH contains a six-residue insertion that extends this loop over the substrate entrance tunnel of a neighboring subunit, thereby obstructing the active site of the adjacent subunit. This feature could be an important factor in the homotropic activation and product inhibition mechanisms. Compared to ALDH1, the substrate channel of NPADH is narrower and lined with more aromatic residues, suggesting a means for enhancing substrate specificity.

This study determined the effect of micronization (high intensity infrared heating) on the concentrations of rapidly digestible starch (RDS), slowly digestible starch (SDS), and resistant starch (RS) in normal barley (NB), high-amylose barley (HAB), and waxy barley (WB). The gelatinized starch contents and the thermal properties of the micronized samples also were determined. Samples of each barley type were tempered to each of three moisture contents (approximately 17, 31, or 41%), and then each tempered sample was micronized to each of three surface temperatures (100, 120, or 140 degrees C). Micronized barley samples were substantially lower in RS and in SDS and, therefore, higher in RDS than corresponding unprocessed samples. In general, higher concentrations of RDS and of gelatinized starch were associated with higher initial moisture contents and higher surface temperatures. The lowest concentrations of RS were observed in micronized WB samples. Similar concentrations of RS were observed in corresponding NB and HAB samples. Micronization resulted in slight increases in the onset (To), peak (Tp), and completion (Tc) gelatinization temperatures and in substantial reductions in the gelatinization enthalpy (DeltaH), the latter reflecting the levels of gelatinized starch in micronized samples, particularly in samples micronized at higher moisture contents and to higher surface temperatures. Endothermic transitions were evident only in samples tempered to 17% moisture or 31% moisture (surface temperature of 100 degrees C only).