Posters

Every year Pion Inc accepts the challenge to present innovative and industry relevant research.  At AAPS 2016 Pion presented 9 posters! They are presented here for you to download, together with previous years' posters.

 

2017 Controlled Release Society Annual Meeting-Boston, MA


 
 
 
 

2016 AAPS Annual Meeting & Exposition


Case studies demonstrating capability of µDISS Profiler, µFLUX apparatus and Au PRO software to determine the degree and extent of supersaturation of amorphous forms and differentiate them from liquid-liquid phase separation.

 

Feasibility study showing application of new device (MacroFLUX) to evaluate and predict the risk of drug-drug interaction based on the flux response.

 

This case study demonstrates ability of in situ concentration monitoring in the simulated mucus fluid as well as ability of µFLUX to reveal if drugs stay supersaturated in the mucus simulated environment

 

Cocrystals are one more tool of formulation scientist to increase solubility of insoluble drug. This study illustrates use of flux measurements to investigate if cocrystal formulations of danazol can improve its bioavailability

 

Ionization properties of drugs determined by pKa are most important phys. chem. characteristics, but it is challenging to measure them when compounds are low soluble. This novel approach uses UV titrations to measure solubility and pKa of the drugs simultaneously

 

Prediction of the food effect on absorption of the drugs is challenging and requires expensive animal studies. This work shows that in vitro measurements using µFLUX device could predict food effect reducing number of animal testing.

 

The flux of several intraconazole formulations were compared to the commercially available product (Sporanox). It was demonstrated that data obtained with µFLUX correlated extremely well with animal studies.

 

This work demonstrates the ability of Skin PAMPA to differentiate and classify the effect of cosmetic solvents on permeation of 2 model compounds, SymWhite™ and Aminexil, and to provide a useful input for formulation development.

 

Novel device MacroFLUX™ that integrates absorption chamber into USP 2 dissolution bath was used to demonstrate that differences in bioequivalence study between benchmark brand name drug and its generic formulation could have been quantitatively predicted by comparing flux measurements for these formulations.

 

2015 AAPS Annual Meeting & Exposition


 
 
 
 
 
 
 
 
 
 

2014 AAPS Annual Meeting & Exposition


 
 
 
 
 
 
 
 

2013 AAPS Annual Meeting & Exposition


 
 
 
 
 
 
 

2012 AAPS Annual Meeting & Exposition


Purpose. Formation of an API (active pharmaceutical ingredient) salt is a common technique for improving the dissolution characteristics and supersaturation of a poorly soluble drug. The supersaturated solution may then precipitate as the free acid or base. The aim of this study was to evaluate the practicality of combining real-time concentration monitoring with fiber optic spectroscopy and powder x-ray diffraction (PXRD) to provide an assessment of salt disproportionation and precipitation.

 

Conclusions. Combining real time in situ monitoring with solid state characterization can provide the preformulation or formulation scientist with a more complete understanding of processes that may suggest drug formulation and development strategies to improve the oral absorption window for a poorly soluble AP

 

Purpose. Solid dispersion technology is used to create amorphous APIs with enhanced solubility potentially leading to improved bioavailability. The objective of the study was to monitor dissolution and precipitation behavior of supersaturating solutions of low soluble compounds. Solubility enhancement was tested using a small-volume in situ UV dissolution apparatus μDISS Profiler™ (Pion Inc.) by collecting concentration-time profiles in biorelevant media (e.g., FaSSIF and FeSSIF).

 

Conclusions. Hot melt extrudates with Copovidone provide opportunity to improve bioavailability of low soluble compounds. The μDISS Profiler allows real-time concentration monitoring of limited amount of material in small volumes of media thus providing a valuable tool for studying meta-stable solubility of amorphous form of API.

 

Purpose. This was aimed at understanding the supersaturation ability of Soluplus with Carbamazepine as a model drug by using real time concentration monitoring.

 

Conclusion. The data suggests that Soluplus maintained the supersaturation of CBZ in simulated media for longer period from the solid solutions. The μDISS Profiler can be used to measure the real-time concentrations of limited amount of drugs for investigating the supersaturation phenomenon.

 

Purpose. This work studied the applicability of a recently introduced skin-mimetic artificial membrane permeability model (Skin PAMPA) to differentiate between topical pharmaceutical formulations. The Skin PAMPA results were compared with data obtained from in vitro Franz cell permeability measurements.

 

Conclusion. The new formulation is demonstrated to be superior in delivering ibuprofen through a skin barrier compared with the commercial benchmark. The Skin PAMPA model can be used with topical formulations to differentiate their ability for transdermal delivery of active pharmaceutical ingredients. Standardization potential and the high-throughput nature of Skin PAMPA can be a valuable cost effective compliment to Franz cell permeability experiments for early skin penetration prediction and topical formulation development.

 

Purpose. The objective of the study was to develop the method of in situ concentration monitoring of free API being released from its nanosuspension without the need for separation of un-dissolved nanoparticles. The comparison of dissolution behavior of micronized and untreated naproxen (API) powder with kinetics of free API release from nano- and microsuspensions was also the goal of this work.

 

Conclusion. Developed method allowed in situ measurement of free API concentration in solution in the presence of nanoparticles. Solubility of naproxen was the same within several standard deviations between all forms of naproxen studied. However dissolution from nanoparticles was practically instantaneous compared to the case of microsuspension or powders.

 

2012 AAPS New England Regional Discussion Group (NERDG)


Purpose.  To prepare and test hot melt extrudates of loratidine or piroxicam with copovidone polymers to improve the API solubility.  A bench-top Dynisco laboratory mixing extruder (LME) was used for preparation of the materials at various temperatures.  Dissolution behavior and solubility enhancement was tested using a small-volume in situ UV dissolution apparatus (μDISS Profiler) to collect concentration-time profiles in biorelevant media such as FaSSIF and FeSSIF.

 

Conclusions.  The supersaturation of piroxicam hot melt extrudates was quasi-stable for more than 24 hours at 3.5 times the solubility of the neat API.  Loratidine extrudates also exhibited a potential for supersaturation as well.  The µDISS Profiler provided concentration-time profiles with high data density without precipitation artifacts caused by liquid sampling.

 

2012 Skin and Formulation Symposium, in Lyon, France


Purpose.  Transdermal delivery has facilitated the development of new drugs during the last few decades.  This work evaluated the interlaboratory performance of Skin PAMPA measurements conducted at Pion and by a well-known pharmaceutical supplier.

 

Conclusions.  As previously reported, Skin PAMPA measurements was highly correlated against Franz cell measurements (human epidermis) using fifteen different APIs.  The Skin PAMPA measurements of seven test compounds as performed in two different labs was in good agreement.  And lastly, both Skin PAMPA and the Franz cell method could easily distinguish between the API permeability in four different formulations.  These observations continue to demonstrate the potential utility of this new technique for rapid screening in a cost effective manner. 

 

AAPS 2011 Meeting and Exposition


Purpose.  To prepare and test hot melt extrudates of Loratidine with Copovidone at 30% and 40% drug loading using a bench-top Dynisco laboratory mixing extruder (LME) at various temperatures. Dissolution behavior and solubility enhancement was tested using a small-volume in situ UV dissolution apparatus μDISS Profiler to collect concentration-time profiles in biorelevant media (e.g., FaSSIF and FeSSIF).

 

Conclusion. Temperature was an important process parameter in preparing amorphous solid dispersions of Loratidine with Copovidone at 30% or 40% API loading on the Dynisco LME. The μDISS Profiler allowed real-time concentration monitoring in small volumes of media thus providing a valuable tool for studying meta-stable solubility of amorphous form of API. 

 

Purpose.  Investigation of the transdermal drug delivery route has intensified recently for both novel and existing drug products. The aim of this work was to adapt the parallel artificial membrane permeability assay (PAMPA) for predicting skin penetration by employing an artificial membrane mimicking the stratum corneum layer of human skin.

 

Conclusions.  The Skin-PAMPA model predicts human skin permeability reasonably well, and because of its standardization potential and high-throughput nature it can be a valuable cost effective alternative to Franz cell studies for early skin penetration prediction. 

 

Purpose.  This study applies to standard 96-well microtitre plate format solubility measurements in fasted and/or fed state simulated intestinal fluids (FaSSIF/FeSSIF). It also introduces a novel automation friendly method of in situ dynamic conversion from simulated gastric fluid (SGF) to FaSSIF while measuring solubility in both media at up to 3 time points.

 

Conclusion.  The high throughput UV-based µSOL method is suitable for accurate solubility measurements in FaSSIF and FeSSIF media in early drug discovery stage and provides better insight into potential in vivo absorption behavior of the drug candidates.  The dynamic assay medium adjustment method allows combination of solubility measurements in SGF and FaSSIF in a single setup thereby minimizing sample consumption. This method provides valuable information about the kinetic of precipitation for the basic compounds and the dissolution of acid compounds relevant under in vivo conditions.

 

AAPS 2011 Emerging Oral Delivery Strategies and Technologies Workshop


Purpose. It has been demonstrated that solubility of practically insoluble compounds can increase several orders of magnitude in more physiologically relevant media like fasted and/or fed simulated intestinal fluids (FaSSIF/FeSSIF) thus providing better understanding of in vivo absorption behavior. It was argued that some drugs could be re-classificatied from BCS Class II into BCS Class I based on their solubility in FaSSIF and FeSSIF.

 

This study adapts solubility measurements in FaSSIF/FeSSIF media to 96-well microtitre plate format enabling screening much earlier in drug discovery/development process.

 

Conclusions. Most of the compounds drastically increased their solubility in FaSSIF and FeSSIF comparing to the corresponding values in FaSSIFblk and FeSSIFblk. For example, solubility of tolfenamic acid increased more than 800 times in FeSSIF (71 µg/mL) compared to its solubility in FeSSIFblk (0.09 µg/mL) while for danazol the ratio between solubility values in FeSSIF (68 µg/mL) and FeSSIFblk (0.23 µg/mL) was around 300. Tamoxifen was fully dissolved in FeSSIF up to a concentration of 147 µg/mL, despite being very poorly soluble in FeSSIFblk (2.3 µg/mL). Solubility enhancement in FaSSIF  ranged from ~ 1 (astemizole) to ~ 95 (danazol).

 

AAPS 2010


Purpose. The salt form of an API (active pharmaceutical ingredient) may dissolve, partially or completely, to transient concentrations above equilibrium solubility levels.  The supersaturated solution may then precipitate as the free acid/base, sometimes coating the remaining input API or formulation, thus significantly modifying the subsequent dissolution rate.  The timeframe of supersaturation and potential precipitation events may have profound effects on bioavailability in vivo.  The aim of this study was to develop a practical and predictive in vitro powder and formulation dissolution method to monitor dissolution and concomitant precipitation processes in biorelevant media. 

 

Conclusions. This novel  in situ monitoring approach to in vitro powder and formulation dissolution/precipitation can provide a fundamental understanding of processes that may be relevant in vivo providing rational approach to formulation design and development. 

 

Purpose.  To optimize pH conditions for Caco-2 assay that allow de-convoluting and understanding various contributions to passive transport of drugs through the cell membrane. The pH and concentration effects on carrier-mediated/active transport were also studied.

 

Conclusion.  A novel approach of optimizing Caco-2 conditions based on predicted results enables the interpretation of difficult measurements with greater level of confidence. The developed approach saves costs, by avoiding poorly-designed assay protocols, and in some cases, avoiding the need for costly measurements.

 

Purpose. A newly developed device was applied to assess the feasibility of performing in situ UV concentration monitoring experiments in 96-well microtitre plate format.

 

Conclusion.  The study confirmed the feasibility of performing in situ dissolution and solubility monitoring in 96-well plate that was not possible before. In addition to high throughput solubility determination, other critical studies such as salt dissolution screening, dissolution/solubility determination in biorelevant media, solubility-excipient screening and others can be performed much earlier in the drug discovery saving costs by dramatically reducing required amount of compounds and expensive reagents. 

 

Purpose.  The objective of the study was to predict human jejunal permeability, Peff, and absorption, %Fa, for a series of fluoroquinolones, using a biophysical model based on measured Caco-2 permeability.  Values of Peff have not been reported for these compounds, and not all of the compounds have reported human absorption values.

 

Conclusion.  Estimates of Peff can be predicted by the biophysical model. From these values, the human absorption may be calculated.  Where absorption comparisons were possible, the agreement was acceptably good.

 

Purpose.  Most of the drug pKa values have been determined at 25°C, instead of physiologically-relevant 37°C.  The aim of this study is to develop a simple model to predict drug pKa values at 37oC from their corresponding 25oC values.  This is expected to improve the in vitro-in vivo correlation (IVIVC) in some cases, and get an improved understanding of the drug absorption process. 

 

Conclusion.  The model we developed is simple to apply to investigative dissolution rate studies done at 37oC, to mechanistic cellular studies, such as Caco-2, as well as to other physiological condition-based measurements. 

 

Purpose.  The aim of the study was to assess how thin PAMPA membrane barriers could be made before they become too fragile or leaky through water pores.

 

Conclusion.  It was shown that antipyrine can have an elevated PAMPA permeability value (from 1 to 5 x10-6 cm/s) in the plates with the thinnest barrier (BD), but it was clear that the plates were too leaky through water pores.  This would limit the application to lipophilic molecules.

 

AAPS 2009


Purpose. A newly developed assay was applied for fast in vitro screening of the effect of various solubilizing vehicles (e.g., 2-hydroxypropyl-b-cyclodextrin (HP-b-CD), polyethylene glycol 400 (PEG400), hydroxypropyl-methylcellulose (HPMC), etc.) and their mixtures on apparent solubility and absorption potential of sparingly soluble compounds.

 

Conclusion.  A new in vitro method facilitates studying of the complex role excipients play in absorption. This low cost high throughput assay enables much more efficient pharmacokinetic studies by pre-selecting most promising formulation vehicles.

 

Purpose. This research investigated the applicability and limitations of a novel approach for measuring intrinsic dissolution rates (IDR) of very small quantities of compounds introduced as powders to buffered solutions and compare these results to disk IDR obtained using the traditional Wood’s apparatus1.

 

Conclusion. Powder IDR measurements can be used in the early stages of drug development, as they use up to 1000 times less API than the traditional Wood’s rotating disk apparatus and are much faster, too. Application of the powder dissolution method to compounds with solubility >1 mg/mL requires additional study.

 

Purpose.  The goal of this study was to measure the apparent solubility of a diverse series of poorly soluble compounds in four different biorelevant dissolution media (BDM, eg. FeSSIF, FaSSIF, and blanks for each) by simulating intestinal conditions to investigate the result in potential BCS classification.  The µDISS Profiler™ allowed simultaneous measurement of dissolution rate and solubility in small volumes of BDM.

 

Conclusion.  All seven compounds displayed higher solubility in FeSSIF than in the corresponding blank buffer. Increased solubility in the BDM resulted in an improved rating in the BCS for cinnarizine, felodipine, indomethacin, terfenadine from class II to class I.  Danazol and glibenclamide remained unchanged.       

 

Purpose.  This study was conducted to assess the permeability of the blood-brain barrier (BBB) to drug-like compounds with a wide range of molecular properties, using the in situ brain perfusion technique in P-glycoprotein (Pgp) deficient [mdr1a(-/-)] mice, and to predict this permeability using an in combo PAMPA (in silico supported parallel artificial membrane permeability assay) model.

 

Conclusion.  The in situ brain perfusion measurements of drug-like molecules, in Pgp deficient mice, can be predicted by an in combo PAMPA method to a satisfactory degree, based on a training set of in situ BBB measurements.  The speed of the PAMPA method, and its substantial lower cost, compared to in vivo measurements, make it an attractive first-pass screening method for BBB passive permeability. 

 

AAPS 2008


Purpose. The objective of the study was to investigate the properties of several of the polymorphs of sulfathiazole using a new miniaturized powder intrinsic dissolution rate (IDR) apparatus, and to relate the IDR values to solubility.

 

Conclusion.  This study successfully demonstrated the application of the new method to simultaneously determine two important properties of the polymorphs of sulfathiazole: (1) intrinsic dissolution rate, and (2) pH-dependent solubility.  Powder IDR measurements can be used in the early stages of drug development since they use up to 1000 times less API than traditional Wood’s rotating disk apparatus and are much faster. 

 

Purpose: To experimentally determine dissolution rate and solubility of a number of poorly soluble drugs with a new miniaturized method.

 

Conclusions: The miniaturized dissolution method is suitable to use also when measuring truly poorly soluble compounds and using biorelevant media. The IDR showed excellent correlation with the apparent solubility values, indicating that the IDR can be used as a substitute for measurement of solubility. Hence, the method allows rapid assessment of dissolution rate and solubility using a small amount of compound only. 

 

Purpose. This research investigated the applicability and limitations of a novel approach for measuring intrinsic dissolution rates (IDR) of very small quantities of compounds introduced as powders to buffered solutions and compare these results to disk IDR obtained using the traditional Wood’s apparatus.

 

Conclusion. Powder IDR measurements can be used in the early stages of drug development, as they use up to 1000 times less API than the traditional Wood’s rotating disk apparatus and are much faster, too. Application of the powder dissolution method to compounds with solubility >1 mg/mL requires additional study.

 

Purpose. This study aimed to investigate the accuracy of software to predict the ionization constants, pKa for a variety of flavonoids.

 

Conclusion. Flavonoids exhibit several challenges to accurate pKa measurement, including low solubility and potential oxidative degradation. Cosolvents ensured that the compounds were completely in solution during the titration. While the assignments made herein are tentative, they suggest that the beta hydroxy group may undergo internal hydrogen bonding that may be incorporated into some commercially available software programs, thus providing better agreement between measured and predicted values. Future work will focus on investigating some of the underlying chemistry further.

 

Purpose. A newly developed assay was applied for fast in vitro screening of the effect of various vehicles (e.g., 2-hydroxypropyl-b-cyclodextrin (HP-b-CD), polyethylene glycol 400 (PEG400, etc.) on solubility and absorption of sparingly soluble compounds.

 

Conclusion. A new in vitro PK method facilitates studying of the complex role excipients play in absorption. Sometimes, individual measurements of permeability and solubility, a task that is especially tedious for sparingly soluble compounds, can be avoided. This practical, low-cost, and relatively high-throughput UV-based assay incorporates the advances achieved in Double-Sink™ PAMPA and is demonstrated to be useful in early lead-investigation screening for formulation effects on absorption.

 

Purpose. The objective was to investigate the feasibility of using a miniaturized disk intrinsic dissolution rate (IDR) apparatus to determine the Biopharmaceutics Classification System (BCS) solubility class while significantly reducing compound consumption comparing to traditional Wood’s apparatus. Additional goal was to develop an approach where IDR measurements performed in media of different buffer capacity could be compared.

 

Conclusion. The results demonstrate that using 100-fold less drug does not sacrifice the quality of the measurement, and lends support to an earlier study1 that the disk IDR measurement may possibly serve as a surrogate for the BCS solubility classification. API-sparing miniaturized IDR measurements can be done much earlier in the drug development cycle.

 

Purpose.  The goal of the study is to predict the pH-dependent permeability profiles of drugs in a Caco-2 assay, based on an in combo procedure using measured PAMPA permeability values and calculated Abraham (alpha, beta, pi, R, Vx) descriptors.

 

Conclusion.  The ability to predict with confidence how Caco-2 permeability will depend on the physicochemical properties of a drug is important in both planning measurements of practically-insoluble molecules and interpreting the results of difficult measurements.  The method we developed appears to be useful in saving cost, by avoiding poorly-designed assay protocols, and in some cases, altogether avoiding the need for the costly measurements.