Determination of solubility by using new methods and techniques μSOL Solubility Systems USP Apparatus 4

1. Perspectives in solubility
measurement
interpretation and
Dissolution
Testing USP 4 (SOTAX)
Dr. Ahmad Abdulhusiaan Yosef
Department of Pharmaceutics
2019/2020
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2. Topic
 Introduction
 Key and Purpose
 μSOL Solubility Systems
 CE 7smart USP Apparatus 4 –
Flow Through Cell Dissolution from SOTAX
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3. Introduction
 Solubility is defined 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)
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4. Introduction
 In the last 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
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5. 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.
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6. 1. μSOL Solubility Systems
 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.
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7. 1. μSOL Solubility Systems
 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
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8. 1. μSOL Solubility Systems Method
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9. 1. μSOL Solubility Systems Application
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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

10. 1. μSOL Solubility Systems Application
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11. 2.CE 7smart USP Apparatus 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.
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13. The Flow-Through Cell Today
 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.
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14. Methodology
 Dissolution Testing according 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

15. Calculation
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16. Methodology
2. Closed Loop Configuration
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.
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17. CE 7smart configurations including:
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.
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18. Other important features include:
 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.
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