Application/Technical Notes

 

AAPS 2016 Posters


Amorphous Solid Dispersions (ASD) of low soluble drugs has become one of the favorite technologies in attempt for improving gastro‐intestinal (GIT) absorption and as a result bioavailability of insoluble compounds. The goal of this study was to apply in situ concentration monitoring for quick assessment of degree and extent of supersaturation that can be achieved by amorphization of the drug. In addition the comparison of the flux through artificial lipophilic membrane from drug loaded below and above their amorphous solubility threshold was investigated.

 

It was demonstrated1,2 that flux measurements provide more in-depth understanding of supersaturated systems than solute concentration measurements alone. This study used miniaturized dissolution – permeation apparatus (μFLUX) to compare flux of itraconazole (Figure 1) from several formulations for which in-vivo rat PK data were available3. The goal of the study was to evaluate the formulation benchmarking ability of the instrumental setup.

 

It was hypothesized and then demonstrated1 that small intestinal mucus layer could stabilize supersaturated state of otherwise precipitating low solubility drugs. It was also concluded2 that flux measurements provide more in‐depth understanding of supersaturated systems than solute concentration measurements alone. This study used miniaturized dissolution – permeation apparatus (μFLUX) to compare flux of carvedilol through artificial membranes from a simple buffer system as well as from media simulating the mucus layer and/or containing solubilizing excipients like hydroxypropyl‐ß‐cyclodextrin.

 

Pharmaceutical cocrystals have emerged as one of the potential strategies to enable supersaturation for poorly soluble drugs and as a result to improve their oral absorption and bioavailability1 . Flux across a membrane provides a better understanding of passive absorption of solutes from supersaturated solutions, since solute activity rather than concentration is the driving force2,3. This study was aimed at investigating how supersaturation of model drug danazol released from its cocrystal in biorelevant media affects the trans-membrane flux of this low soluble compound.

 

For generic drug development traditional (USP) dissolution tests have been used in the pharmaceutical industry to compare performance of different drug product formulations before or instead of conducting bioequivalence studies. Although dissolution tests provide a simple way of testing formulations, the in vivo predictive power of these tests are questionable. Namely, when a poorly water-soluble API is formulated to enhance its dissolution, additives, such as surfactants and polymers have an effect not only on dissolution profile, but also on flux through the membrane. The aim of this study was to represent the importance of simultaneous dissolution-absorption studies using MacroFLUX apparatus before conducting bioequivalence studies.

 

It has been shown that a miniaturized two‐stage in vitro dissolution test1 can be used to understand why some low‐soluble weak basic drugs show reduced or highly variable absorption when co‐administered with pH‐modifying agents. The goal of this study was to demonstrate that an absorption chamber combined with USP I and II dissolution apparatus can be used to study similar drug‐drug interactions (DDI) of the final dosage forms.

 

The food effect on absorption can be attributed to the different mechanisms and it is often difficult to predict while pharmacokinetic (PK) studies are expensive and may have big variability. Recent studies1,2 demonstrated that flux measurements provide better insight into complex relationship between thermodynamic activity and equilibrium solubility of the low soluble compounds in the presence of excipients (e.g. components of the simulated intestinal fluids).


This work aimed to introduce an in vitro method for qualitatively estimating food effect in early stages of pre-formulation and formulation based on the differences in the flux through artificial lipophilic membranes of two chamber dissolution-permeability system.

 

FLUX


This technical note introduces devices that can be utilized for flux measurements in a systematic and reproducible manner. The small volume apparatus called μFLUX is compatible with Pion’s mini-bath (MB-8) and can be used on various stages of formulation development when amount of API and/or its formulations is limited while many permutations of different formulation strategies have to be investigated. The other device MacroFLUX is an absorption chamber insert into USP 1 or 2 dissolution bath vessels. Both apparati would allow assessment of complex interplay between solubility, permeability and dissolution rate in formulation development and would provide valuable tools for in vivo predictive in vitro studies.

 

PULSE™


The pKa determination by UV titration relies on the differences in molar absorptivity between charged and uncharged species present in solution[1]. The traditional UV titration of a compound takes about 25–30 minutes. The fast UV titration method utilizes Pion’s linear universal buffer Prisma™ HT. It enables replacing a variable volume titrant addition with a constant volume addition that produces predictable pH change with each dispensed aliquot of KOH or HCl. This technical note demonstrates that reducing the number of titration points while keeping their uniform distribution along pH axis produces comparable results to the regular UV titrations while reducing the assay time to 7–10 minutes per titration. Additional potential benefit of fast titrations is that low-soluble compounds can stay supersaturated for a short period of time. That may enable aqueous pKa measurements for some low-soluble compounds that otherwise have to be determined only with the presence of cosolvent. It can also benefit compounds that are not stable and would decompose during the long assay.

 

PAMPA


Applying transdermal patches to deliver active pharmaceutical ingredients (API) through the human skin provides numerous advantages compared to traditional dosage forms. Therefore, more and more efforts are devoted to the development of these formulations. To help the evolution of the patches, Skin PAMPA provides a unique opportunity to continuously estimate the performance of the patch during the early stages of development. This can help the formulator test various combinations, aiming to reach the most promising matrix for each API.

 

Studying the permeation properties of formulations is crucial in all stages of dermal and transdermal formulation development. Most of the available methods suffer from being labor-intensive and having poor reproducibility. Skin PAMPA technology is a useful tool for the early stages of development as it is an easy-to-use, cost-effective, and standardized model with significantly lower variation compared to most of the available methods. This technical note provides an example of studying three commercially available diclofenac formulations using Skin PAMPA model.

 

µDISS Profiler™


Nanoparticle formulations of active pharmaceutical ingredient (API) are often made in the form of a suspension with addition of surfactants to prevent nanoparticles from aggregating. The concentration of dissolved API in the nanosuspension is often unknown and determining the solubility of API when nanosuspension is added to the assay media is challenging. This technical note will describe the use of Zero Intercept Method (ZIM) implemented in Au PRO™ software to resolve these issues.

 

Because of its well characterized fluid hydrodynamics, the rotating disk method is a useful tool for mechanistic dissolution studies. The disk intrinsic dissolution rate (DIDR) measurements have been used to characterize solid drugs, including studies of dissolution-pH rate profiles in the presence of buffers, complexing agents, and various excipients. It is currently debated at the FDA whether the DIDR method can be used to determine solubility class membership in the Biopharmaceutics Classification System, with encouraging early indications.