New methods of solubility

New methods of solubility

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  Perspectives in solubility measurement interpretationand Dissolution Testing USP 4 (SOTAX) Dr. Ahmad Abdulhusiaan Yosef Department of Pharmaceutics 2019/2020 1
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  Topic  Introduction  Keyand Purpose  μSOL Solubility Systems  CE 7smart USP Apparatus 4 – Flow Through Cell Dissolution from SOTAX 2
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  Introduction  Solubility isdefined as the amount of substance that passes into solution to achieve a saturated solution at constant temperature and pressure. Solubility are expressed in terms of maximum volume or mass of the solute that dissolve in a given volume or mass of a solvent.  To come out from the traditional methods that have been used to determine the solubility PH-profile , here we will address issues of measurement and interpretation of pH dependency in solubility profiles.  During drug development, in vitro dissolution methods are applied to optimize the delivery profile of the dosage form. A prerequisite for the utility of this is that the selected in vitro methods are predictive of the in vivo outcome.  The modification of the dissolution medium can also increase the solubility of the drug substance by addition of surfactants (above their CMC), complexing gent (e.g. cyclodextrins), or organic solvents . The major drawback for these two options is that the dissolution medium composition and volume will not be biorelevant.(NOT mimic intestinal fluid) 3
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  Introduction  In thelast decades, several new drug classification systems have been described to evaluate the potential difficulties of developing a given drug.  These classification systems are the Developability Classification System (DCS) and the refined DCS, both based on the dissolution rate and solubility of the drug in biorelevant media, as well as the permeability.  In this short presentation will show new methods that have been used to measure and interpretation of solubility and dissolution rate apparatus SOTAX , which are considered not the same traditional or conventional methods that used earlier .  1. μSOL Solubility Systems  2. CE 7smart USP Apparatus (4) Flow Through Cell Dissolution from SOTAX 4
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  Key and Purpose Keys: miniaturized shake flask method to 96-well microtitre plate and Dissolution apparatus USP 4 Purpose : The purpose of this presentation is to give an introduction to the study solubility PH-profile and dissolution apparatus 4 in the Pharmacopeial area to provide you with more options to choose the µSOL System that fits the economical budget and needs . In addition the Flow Through Technique is able to fulfill the requirements of novel formulations. Its flexibility and ability to characterize the release properties of a wide variety of formulations make it a powerful tool for pharmaceutical development. 5
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  1. μSOL SolubilitySystems  What are µSOL Solubility systems? (muon separator on-line)  The µSOL Systems implement innovative miniaturized shake flask method to 96- well microtitre plate format. One point calibration is prepared for up to 96 studied compounds. The method is easily adaptable to work with either neat API or DMSO stock solution. Solubility can be measured in aqueous buffers, with the presence of solvents and excipients as well as in simulated intestinal fluids like FaSSIF and FeSSIF. Patented UV processing software analyzes full spectra and detects impurity and decomposition of the studied compounds based on changes in their spectral characteristics. Thermodynamic or kinetic solubility can be measured and external LC equipment may be used if required.  A complete, turnkey solution that will have you confidently measuring solubility vs. pH, in biorelevant media. 6
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  1. μSOL SolubilitySystems  Instrument and Materials 1. Miniaturized shake flask of 96-well microtitre plate format each micro-well is about 150 µm ( r & h ) that enabling it to analyze 1500 small chemical components all in one cycle. 1. Works with either neat API or DMSO stock solution 2. Simulated intestinal fluid like FaSSIF and FeSSIF ( fasted state gastric or intestinal fluid ) ; To make 1.000 L of FaSSIF Prepare buffer Dissolve: 0.420 g of NaOH (pellets), 3.438 g of NaH₂PO₄ Anhydrous, 6.186 g of NaCl, in about 0.900 L of purified water. Adjust the pH to 6.5 with either 1 N NaOH or 1 N HCl. Make up to volume (1.000 L) with purified water at room temperature. 3. Built in patented UV processing quantitation software. 4. Detector from 50 ng/mL up to 2 mg/mL of full spectral shape analysis for impurity/decomposition detection 7
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  1. μSOL SolubilitySystems Method 8
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  1. μSOL SolubilitySystems Application 9 1. Methods Determine solubility with sub-micro=molar detection limit – saving precious API 2. Easy to use – quickly start measuring solubility 3. Instantly analyze data – using a user-friendly interface software with advanced data processing 4. Leverage our science and expertise – use advanced software tools to interpret solubility-pH profiles 5. Save time – eliminate time-consuming standard curve preparations 6. Using any media – generate unique and creative solubility assays using Pion’s open platform 7. Aqueous Solutions Analyzing 8. Building Structure Activity Relationships (SAR) 9. Biorelevant Media Studying: FaSSIF, FeSSIF, Simulated Gastric Fluid (SGF) 10. Selecting Thermodynamics or Kinetic Conditions 11. High-Throughput Solubility at a Single pH
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  1. μSOL SolubilitySystems Application 10
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  2.CE 7smart USPApparatus 4 - Flow Through Cell Dissolution from SOTAX  Overview Your Experts in USP Apparatus 4 Flow Through Dissolution Testing New types of formulations and drug delivery technologies call for a new approach to in-vitro drug release testing. Traditional dissolution methods are not tailored to these novel dosage forms. The flow through technique is able to fulfill the requirements of such complex formulations. Its flexibility and ability to characterize the release properties of a wide variety of formulations make it a powerful tool for pharmaceutical development.  Acceptance by Regulatory Authorities Worldwide The method became an official compendial apparatus when it was accepted by the US and European Pharmacopoeia in 1990 followed by the JP in 1996. Today, USP Apparatus 4 can be found in USP <711> Dissolution for Immediate Release Dosages and USP <724> Drug Release for Extended Release testing. It describes the specifications for the instrument, flow cells and methodology. Today, several monographs and NDAs have been approved by health authorities. 11
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  The Flow-Through CellToday  Flow-Through Cell is widely recommended for 1. Poorly soluble, modified release and extended release tablets, and medical devices. 2. Evolution of new drug delivery platforms 3. Suspensions, injectable, drug coated medical devices, parenteral formulations, implants, gels, ointments, creams, liquids, ophthalmic solutions and lenses, suppositories, soft gelatin capsules, beads, granules, APIs, microspheres and more. 4. For most novel dosage forms and was used for the first accepted submission for a drug-eluting stent on the market. 13
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  Methodology  Dissolution Testingaccording to the Flow-Through Method In the Flow-Through Method, the test sample is located in a small volume cell through which media is pumped at a temperature of 37 °C. The eluate is filtered upon leaving the cell and then can be analyzed directly or collected in fractions to calculate the percent drug release. There are two types of configuration 1. Open Loop Configuration For poorly soluble compounds the Flow-Through is linked to “optimal sink conditions” In the “open loop” configuration, fresh media crosses the dosage form. It is also possible to change the type of media that passes through the flow cell after predefined time intervals. This feature is useful for performing IVIVC studies where the dosage form naturally passes through the different pH of the digestive tract within sink conditions. USP 4 maintains temperature control and dosage integrity even on disintegrating and light sensitive formulations. The Flow- Through Method is the only method that allows for a media change on a suspension and a powder. 14
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  Calculation 15
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  Methodology 2. Closed LoopConfiguration In a closed system, the Flow Through Method is conducted much like USP Apparatus 1 and 2 where a fixed volume of media circulates across the dosage form. Samples can be taken a predetermined time by an auto-sampler, read by an on-line UV or a fiber optic probe. Results of drug dissolved are expressed as a cumulative dissolution curve. Closed systems are ideal for dosage forms where solubility and sink conditions are optimal in a volume range from 50 ml to 2 L. 16
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  CE 7smart configurationsincluding: 1. Automated On-line with spectrophotometer (open and closed loop) 2. Automated On-/Offline with spectrophotometer and fraction collector (open loop) 3. Automated media changes SOTAX is also essential in the calculations involved in open and closed loop configurations. For closed loop systems, % dissolved much like USP 1 and 2 using a fixed volume. For open loop system, % dissolved is calculated where the measurable active at a particular time interval is proportional to a defined volume that has passed through the cell. SOTAX automatically converts the % dissolved data into a cumulative release profile. 17
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  Other important featuresinclude:  User-friendly method set up, results reporting, hardware control  Real time data collection in % dissolved, abs or concentration  Single or multi-component analysis  Placebo or impurity subtraction  Standard Calibration and standard bracketing  Flow rate and temperature reporting  Control of UV (different drivers available), sampling time points, sample volume collection  Cell Grouping allows the collection of data by grouping different cells with different testing conditions (e.g. different flow rates, different dose etc.).  Qualification requirements for USP Apparatus 4 temperature and flow rate of the pump be qualified at regular 6 month intervals. 18
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