For generic formulation development, traditional (USP) dissolution tests provide primary input parameters for predicting in vivo performance of different drug formulations before conducting bioequivalence studies. Although USP dissolution tests are relatively simple to conduct for testing formulations, the in vivo predictive power of these tests is questionable1. Namely, when a poorly water-soluble API is formulated to enhance its dissolution, additives, such as surfactants, polymers and cyclodextrins have an effect not only on dissolution profile, but also on flux through the membrane.
|Subcutaneously administered biopharmaceuticals|
A novel in vitro method for predicting how the characteristics of the subcutaneous tissue may influence the post-injection stability and diffusional properties of subcutaneously administered biopharmaceuticals has been developed. Scissor subcutaneous injection site simulator mimics the human body conditions and allows to understand how a formulation influences the behaviour of a biotherapeutic in the subcutaneous (SC) injection site. This allows to expedite the identification of lead formulations with optimal absorption properties following injection and facilitating rational formulation design.
|Scissor subcutaneous poster|
The subcutaneous(SC) route of administration has gained much interest in recent years, showing higher levels of patient compliance than current IV methods and giving a cost-effective alternative for health organizations. For this reason, a better understanding in vivo behavior of these types of formulations is essential for more insightful development and application of these drugs in the future.
|Measuring the isoelectric point of peptides by potentiometric titration|
The isoelectric point (pI) is the pH at which biological amphoteric molecules such as peptides and proteins carry no net electrical charge. Biopharmaceutical drug formulations that are intended for subcutaneous injection are often prepared at about pH 4 to enhance shelf life but when they are injected into the body the pH swiftly moves to 7.4. If the isoelectric point is between these pH values, there is increased risk of precipitation and aggregation after injection, which could diminish bioavailability. Isoelectric point values can be calculated precisely for molecules with only two ionizable groups, but are harder to estimate as the number of acidic and basic groups increases. Isoelectric point values are traditionally measured by electrophoresis, but here we present the measurement by potentiometric titration. This method has the advantage of high precision.
|Behavior of Basic Compounds in the Presence of Plasdone Polymers|
To study the solubility and supersaturation behavior of different basic compounds in the presence of Plasdone polymer.
|Estimating Food Effect on Drug Absorption using Flux Experiments through Artificial Lipophilic membranes|
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.
|Application of MacroFLUX™ Apparatus for Screening Formulations before Bioequivalence Studies|
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.
|Study of Danazol Cocrystal Using Trans-Membrane Flux Measurements|
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 bioavailability . 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 force. 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.
|Degree and Extent of Supersaturation of Amorphous Pharmaceuticals and Their Flux through Lipophilic Membrane|
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.
|AN418 Using Scissor as a platform to analyze non-protein subcutaneous formulations|
Subcutaneous (SC) therapies have gained more importance over the years due to their favourable ability to administer chronic therapies in comparison to their intravenous (IV) counterparts. Furthermore, with the ageing of the world population, it is of particular importance to reduce the burden of the health services. Since SC formulations do not require supervision by medical professionals to be administered, they present an excellent alternative to the current intravenous therapies.
Even though the majority of SC formulations consist of biopharmaceuticals, some formulations contain a non-protein molecule as an Active Pharmaceutical Ingredient (API).
|AN501 A novel in vitro model for subcutaneous injection|
The Scissor is a new instrument designed to simulate the physiological conditions of the hypodermis, to be used as an in vitro model of the physical behaviour of biopharmaceutical formulations undergoing subcutaneous (SC) injection.
Often biopharmaceuticals are formulated under non-physiological conditions with the aim of improving stability and prolonging shelf-life. Biopharmaceuticals intended for SC injection are typically formulated at low pH to mitigate decomposition, and in the presence of various stabilising agents and excipients.
|AN502 IN vitro studt of subcutaneous injection of two insulin formulations|
Insulin is a peptide hormone produced in the pancreas. It is used to regulate blood glucose levels by promoting the absorbance of glucose from the blood stream and inhibiting the production of glucose by the liver.
|AN503 Investigation of subcutaneous monoclonal antibody formulations|
There is a strong patient preference for subcutaneous (SC) delivery of parenteral drugs. SC therapies are safer to administer and less time-consuming than intravenous (IV) therapies and they do not require supervision by medical professionals, making them
suitable for self-managed home care treatments.
|AN01 High quality measurements for small sample amounts|
A comprehensive validation study conducted using the SiriusT3 instrument has demonstrated that highly accurate and repeatable data are obtained for key physico-chemical parameters using sub milligram amounts for pKa and logP measurements and from as little as 2 mg for solubility measurements. The study compared results obtained from Pion standard assays with literature values and excellent agreement was demonstrated.
|AN02 PKa measurements in 15 minutes – the SiriusT3 Fast UV pKa method|
Understanding the ionisation properties of a molecule is an essential requirement for drug development. SiriusT3 technology provides the capability to perform pKa measurements in 15 minutes using only 5 µL of a 10 mM stock solution. This method requires that the molecule exhibits discernable UV absorption changes on ionisation and possesses an intrinsic aqueous solubility greater than 30 µM. Compounds having a lower aqueous solubility can be accommodated using a cosolvent assay.
The SiriusT3 Fast UV pKa method has been validated against results reported in the literature and produces results that are of comparable quality to those obtained by traditional methods. Measurement repeatability is typically within 0.01 pKa units. A complete summary of the data collected in this study is available on request.
|AN04 Insights into BCS classification using Pion assays|
This application note describes how the Pion Cheqsol solubility assay and Log P measurements can give useful insights into the BCS class of your compound.
|AN06 The use of cosolvent pKa assays for poorly soluble compounds|
The ionisation constant or pKa is a solution property of a compound. The formation of a precipitate during a pKa acid/base
titration therefore prevents the accurate measurement of pKa. However, drug-like molecules are often poorly soluble in water. In these cases, a cosolvent mixture comprising water and a water-miscible organic solvent can be used to enhance solubility. By performing titrations in several different solvent / water ratios, the pKas of water-insoluble compounds can be derived using the well-known Yasuda-Shedlovsky extrapolation.
|AN08 Solubility and Supersaturation – A Brief Introduction|
Solubility is a key pharmaceutical parameter. For pharmaceuticals, the solubility in two types of media are important: aqueous based fluids such as the gastrointestinal tract fluid and blood, and lipid based media such as cell membranes and micelles.
Most biochemical and pharmacological processes occur in aqueous media and determining the solubility of a drug in an aqueous based medium is a very important part of drug development. This application note briefly introduces some relevant
terminology and methods of determining solubility.
|AN09 The Determination of Solubility – Pion CheqSol Explained|
The CheqSol method accurately determines the kinetic and intrinsic solubilities of ionizable compounds. It generates detailed information about the extent and duration of supersaturation and a pH-solubility profile from a single, highly automated assay which takes less than 2 hours. This application note provides a brief overview of the technique and should be read alongside Application Note 08/12, Solubility and Supersaturation —A Brief Introduction, which describes some terminology associated with solubility determination.
|AN13 Measuring Solubility What’s Best for You?|
This application note focuses on three solubility assays:
1. Screening assay
2. Shake-flask equilibrium assays
3. pH-metric solubility assay
|AN410 Measuring the isoelectric point pf peptides by potentiometric titration|
The isoelectric point (pI) is the pH at which biological amphoteric molecules such as peptides and proteins carry no net electrical charge. Biopharmaceutical drug formulations that are intended for subcutaneous injection are often prepared at about pH 4 to enhance shelf life but when they are injected into the body the pH swiftly moves to 7.4. If the isoelectric point is between these pH values, there is increased risk of precipitation and aggregation after injection, which could diminish bioavailability.
|AN402 Controlled supersaturation assays for modelling intestinal precipitation|
Controlled supersaturation is now fully supported in a commercial instrument. Pion inForm provides a robust protocol for this assay, as described below.
|Triclosan: a PhysChem study|
A PhysChem study was carried out using the Pion inForm, to observe the solubility, supersaturation, precipitation and dissolution behaviour of the compound.
|BCS Class IV formulation: case study|
Overcoming the difficulties posed by BCS Class II and IV APIs, where oral bioavailability is typically poor, is a challenge for modern formulation development. Although dissolution instrumentation is prevalent, most types of apparatus are not designed to simulate physiological conditions and their in vivo predictive power is poor. An instrument that has the ability to predict formulation behaviour in vivo would, therefore, be a useful tool for formulators looking to understand how their formulation was likely to perform in animal testing and clinical trials. The Pion inForm is an automated robotic, titrator that has the capability to test multiple formulation types using a variety of assays designed to mimic the dynamic chemical environment of the GI tract.
|Comparison of Naproxen Release from Nano- and Microsuspensions with Its Dissolution from Untreated and Micronized Powder|
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.
|Skin-PAMPA: A New Method for Fast Prediction of Skin Penetration|
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.
|Preparation, Physical Characterization and Solubility-Dissolution Testing of Loratidine Hot Melt Extrudates Prepared on a Laboratory Mixing Extruder|
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.
|Evaluating Drug Salt Dissolution and Precipitation Processes for Rational Formulation Strategies|
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.
|Developing Skin PAMPA for Transdermal Patches|
In the present study commercially available transdermal patches (3 nicotine, 2 fentanyl, 1 rivastigmine and 1 ketoprofen) are studied. Data are compared to the declared permeation speed that is indicated by the manufacturers.
|Univ Potentiometric Sensors Food Matrixes|
In this study we evaluated the applicability of universal potentiometric sensors to monitor concentration of API in situ for real food samples. It will be demonstrated that the measurements can be performed not only in liquid food (beer, wine and sodas) but also in suspended solid food such as noodles and steak and this without any sample preparation.
|Supersaturation and Transmembrane Flux of Meloxicam|
This study was aimed at comparing the supersaturation ability of Soluplus® and Kollidon® VA 64 with low soluble compound Meloxicam as a model drug by using real time concentration monitoring and dissolution – permeability setup.
|Evaluation of Optimized Caco-2 Permeability Measurements|
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.
|Nanoparticle Formulation of Gresiofulvin|
Recently developed Zero Intercept Method (ZIM) enabling, for example, in situ concentration monitoring of free API being released from nanoparticles was applied to determine solubility and dissolution of gresiofulvin formulated as nanosuspension. The effect of formulation was also studied through miniaturized dissolution-permeability setup (µFLUX) to determine if nanosuspension formulation improves flux of the griseofulvin through artificial membrane.
|Very Thin PAMPA Membranes Indicate Higher Antipyrene Permeability but are Fragile and Contain Leaky Water Pores|
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<sup>-6</sup> 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.
|Prediction of in situ Blood-Brain Barrier Permeability using BBB PAMPA Model|
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.
|Impact of Biorelevant Media on Apparent Solubility and Biopharmaceutical Classification of Poorly Soluble Compounds|
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.
|In Situ Solubility and Dissolution of Concentrated Solutions|
The aim of this study was to evaluate applicability of Attenuated Total Reflection (ATR) UV probes to accurately measure highly concentrated solutions in real time with no need for dilution and solid separation.
|Drug Permeation in Skin PAMPA and Franz Cell Model|
The aim of this study was to compare drug permeation in Franz diffusion cells using porcine skin and in the Skin PAMPA model. Ibuprofen, caffeine and Uvinul A Plus (Table 1) were selected as the model permeants as they represent respectively, a lipophilic and hydrophilic skin permeant and a compound which resides largely on the surface of the skin.
|Penetration Enhancer Effect of Sucrose Esters|
The permeability measurements were performed by ex vivo Franz diffusion cell method and a newly developed Skin-PAMPA model. Franz diffusion cell measurement is a commonly used research tool for studying diffusion through in vitro synthetic membranes or penetration through ex vivo human skin, while Skin-PAMPA is a recently published technology for the fast prediction of skin penetration. Transdermal preparations were investigated containing 2.64% concentrations of different SEs and/or TR, while the IBU concentration (5%) has been kept constant to be able to see the effect of penetration enhancers
|Novel in vitro PK (non-animal PK) Assay for Excipient/Vehicle Formulation Studies|
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.
|gut-box pampa-evolution pampa-explorer-frontier|
|Comparison of Miniaturized Intrinsic Dissolution Rate Measurement to Traditional Wood’s Apparatus|
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.
|Prediction of Caco-2 pH-Dependent Permeability based on High Quality in vitro Training Set|
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.
|Determination of the Intrinsic Dissolution Rate (IDR) from a Powder and using a Miniaturized Wood’s Apparatus|
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.
|Dissolution Rate and Apparent Solubility of Poorly Soluble Compounds in Biorelevant Fluids|
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.
|Cyclodextrin-Based Orally Fast Dissolving Drug Delivery System of Aripiprazole and Its In Vitro Dissolution-Permeation Testing Using µFLUX|
The formulation development for a poorly water soluble antipsychotic drug aripiprazole is presented using µFluxTM apparatus, a technique, which, besides measuring dissolution follows the flux at the same time enabling to achieve better in vitro-in vivo correlation.
|Dissolution, Free Drug Concentration and Permeability of Crystalline Nanoparticle Formulation Study Using In Situ Fiber Optic and Potentiometric Techniques|
The purpose of this study was to determine applicability and limitations of two in situ methods (spectroscopic UV-vis and potentiometric) in their ability to measure free drug concentration in the presence of nanoparticles.
|Interplay between Ketoconazole Cocrystal Supersaturation and Trans-membrane Flux Behavior In Simulated Intestinal Fluids|
This study was aimed at investigating how cocrystal coformers affect the trans-membrane flux in the in vivo relevant dissolution – permeability setup
|Application of Skin Pampa™ to Cosmetic Solvent Screening|
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.
|Differentiating itraconazole formulations based on the flux through artificial lipophilic membranes|
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.
|Using Integrated Absorption Chamber with USP II Dissolution Apparatus to Predict Risk of Drug–Drug Interaction from pH Modifying Agents|
Feasibility study showing application the MacroFLUX to evaluate and predict the risk of drug-drug interaction based on the flux response.
|Using flux experiments through artificial lipophilic membranes for predicting food effect for BCS Class 2 Compounds|
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.
|µDISS Profiler™ in Early Pharmaceutical Development: Miniaturized Intrinsic Dissolution Rate (Mini-IDR™) Measurement of GRISEOFULVIN and CARBAMAZEPINE|
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.
|Studying transdermal patches using Skin 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.
|gut-box pampa-evolution pampa-explorer-frontier|
|Studying semi-solid formulations of diclofenac using Skin PAMPA|
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.
|gut-box pampa-evolution pampa-explorer-frontier|
|Measuring Solubility of Nanoparticles by Zero Intercept Method|
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.
|FLUX Measurements using Pion µFLUX™ and MacroFLUX™ Devices|
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.
|Study of Danazol Cocrystal using Trans-membrane Flux Measurements|
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
|Using Integrated Absorption Chamber with USP II Dissolution Apparatus to Predict Risk of Drug‐Drug Interaction from pH‐Modifying Agents|
It has been shown that a miniaturized two‐stage in vitro dissolution test 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.
|Effect of Simulated Mucus Environment on the Supersaturation of Carvedilol and Its Flux through Artificial Lipophilic Membranes|
It was hypothesized and then demonstrated that small intestinal mucus layer could stabilize supersaturated state of otherwise precipitating low solubility drugs. It was also concluded 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.
|Differentiating Itraconazole Formulations Based on the Flux through Artificial Lipophilic Membrane|
It was demonstrated 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 available. The goal of the study was to evaluate the formulation benchmarking ability of the instrumental setup.
|Using Skin-PAMPA For Transdermal Patch Testing|
Using the skin as absorption site presents unique challenges that have facilitated the progression of transdermal drug delivery in the past decades. Efforts in drug research have been devoted to find a quick and reproducible model for predicting the skin penetration of molecules, because the in vitro or in vivo animal models are expensive, labor-intensive and suffer from poor reproducibility.
The Parallel Artificial Membrane Permeability Assay (PAMPA) 1 has been extended for prediction of transdermal penetration by developing the “skin-mimetic” artificial membrane 2. Having a high standardization potential and being a high throughput method, PAMPA can become an ideal model for prediction of skin penetration in early stages of drug development. In the present study commercially available transdermal patches (3 nicotine, 2 fentanyl, 1 ketoprofen) are studied. Data are compared to the declared permeation speed that is indicated by the manufacturers.
|Novel HT Method for Parallel Excipient/Vehicle Formulation Studies|
A newly developed 96-well based assay was applied for fast in vitro screening of the effect of various formulation vehicles, as well as micronization and micelle formation on relative absorption enhancement for sparingly soluble compounds using artificial membranes.
|Dissolution-Permeability Apparatus with Integrated In Situ Concentration Monitoring of both Donor and Receiver Compartments|
Development strategies for insoluble compounds require not only measurement of solubility enhancements achieved through formulation but also assessment of the effect a formulation has on permeability. An new dissolution-permeability measurement platform (µFLUX™) allows simultaneous monitoring of both effects thereby providing an in vitro path to early in vivo predictive biorelevant absorption testing.
|Universal Potentiometric Sensors: Application for Real Time Concentration Monitoring in Complex Biorelevant Media|
Up till present the use of universal potentiometric sensors in surfactant containing media was problematic. Typical issues arising are: slow response, limited sensitivity and short lifespan. In this study we will show that the free drug sensors can be used in media containing up to 5% surfactant and that the above mentioned issues can be satisfactory resolved. The products Brij-35 ® Tween 20 ® and Tween 80® were tested.
|Assessment of Transdermal Penetration Enhancement by Topical Pharmaceutical Excipients Using Skin PAMPA Method|
BASF Pharma Ingredients and Services offers our solutions-oriented Skin Delivery Platform to formulators of OTC and Rx topical products. This platform provides insights and materials to meet needs in Topical Drug Delivery, Mildness, Wound Care and Skin Sensory. In this work, Topical Drug Delivery is highlighted in a joint study with Pion, Inc. to evaluate the permeability of an API (sodium
ibuprofen) across an artificial skin-mimetic membrane assisted by various dermatology excipients as a means to assess their use as skin penetration enhancers for topical application. Three broad classifications of materials were tested, emollients as the classical penetration enhancer, as well as solvents and emulsifiers for use in a wide variety of topical product forms.
|Dissolution and Precipitation Monitoring of Crystalline Salts|
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
|Soluplus® Maintains the Supersaturation of Carbamazepine from Amorphous Solid Dispersions|
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.
|Application of Skin PAMPA to Differentiate Between Topical Pharmaceutical Formulations of Ibuprofen|
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.
|In Situ Monitoring of Supersaturation State for Solid Dispersions of Low Soluble Compounds|
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.
|Monitoring Supersaturation State of Solid Dispersions of Low Solubility Compounds|
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.
|Skin-PAMPA: Fast Prediction of Skin Penetration|
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.
|Novel Device and Method for in situ UV Dissolution and Precipitation Monitoring in 96-well Plate|
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.