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MINOR PROJECT MID-REVIEW

“Bioavailability Enhancement of
Commonly Available
Class II and Class IV Drugs through
Surface Modification”

Submitted By:
Anshul Kestwal, Harshit Belwal, Latika Sharma and Ozair Ansari
CONTENTS
 Introduction
 Solubility Enhancement Methods
 Drug Properties Data
 Experimental Progress
 Modification in Plan
 Conclusion
 References
INTRODUCTION
A PEEP INTO THE PROJECT BASICS
PROJECT OBJECTIVE
 To select some cheaply available low solubility, low bio-
availability common class II and class IV drugs.
 To enhance the amorphousness (surface area) of insoluble or
poorly soluble crystalline class II and class IV drugs via solvent
and anti-solvent routes.
 To enhance the bio-availability of the above medicines via surface
modification observed through UV vis analysis.
PHARMACEUTICAL DRUGS

 Chemical substances used for treating, curing and preventing different types of
diseases.
 Commonly referred to as medicines or medication, pharmaceutical drugs are used
in the medical diagnosis, treatment, prevention or cure of disease.
 Discovery and Development: an expensive endeavour.
 Classified in various ways:
 Usage
 Solubility and Permeability
 Potentiality of Abuse
CLASSES OF DRUGS
BIOPHARMACEUTICAL CLASSIFICATION SYSTEM

Solubility Permeability

High Low
High Class I Class III
Propanolol, Verapemil, Neomycin, Ranitidine, Peptites,
Metoproplol, Salicylic Acid, Enalprilate, Cetirizine, Folinic
Diazepam, Caffeine, Glucose Acid

Low Class II Class IV


Paracetamol, Ketoconazole, Clorthiazide, Tobramycin,
Nicardipine, Mefanimic Acid, Flurosemide, Cefuroxime,
Nisolidipine, Diclofenac, Neomycin
Erythromycin, Ibuprofen
BIO-ACTIVITY & BIO-AVAILABILITY
• Biological Activity or Pharmocological Activity describes the effects (desireable and
adverse) on the living tissue.
• Chemical Drugs are complex by nature; controlled by active ingredient or pharmacophore, but
can be modified by the other constituents
• Pharmacological/biological activity plays a crucial role: suggests uses of the compounds in the
medical applications.
• In pharmacology, bioavailability (BA or F) is a subcategory of absorption and is the fraction
of an administered dose of unchanged drug that reaches the systemic circulation, one of the
principal pharmacokinetic properties of drugs.
• By definition, when a medication is administered intravenously, its bioavailability is 100%.
However, when a medication is administered via other routes (such as orally), its bioavailability
generally decreases (due to incomplete absorption and first-pass metabolism) or may vary from
patient to patient.
• Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be
considered when calculating dosages for non-intravenous routes of administration.
PROJECT RELEVANCE TO CHEMICAL
ENGINEERING
 The Application and Relevance of this study is crucial with respect to various
disciplines of Core Chemical Engineering.
 The process of the project is a direct application of Particulate Technology
(Mechanical Operations), Chemical Thermodynamics and other allied sciences
like Chemical Process Calculation.
 These include the liquid-solid, and liquid-liquid solution behavior, the action of
solvent and anti-solvent on the drug API and more.
 Moreover, the far reaching applications of the pharmaceutical industry, an
offshoot of the mother lode of core chemical engineering applications, make this
project an excellent exercise in scientific investigation as well as training.
PHYSICAL METHODS
 The systems that are developed for class II drugs are based on the
Micronization, Lyophilization, Addition of Surfactants, Formulation as
Emulsions and Microemulsion Systems, Use of Complexing Agents Like
Cyclodextrins, and so on.
 The class IV drugs present a major challenge for the development of drug
delivery systems and the route of choice, due to their poor solubility and
permeability characteristics. These are often administered by Parenteral
Route, with the formulation containing solubility enhancers.
 Particle size reduction like Nanosuspension, modification of the crystal
habit like Polymorphs, Amorphous Form and Co-crystallization, drug
dispersion in carriers like Eutectic Mixtures, Solid Dispersions, Solid
Solutions and Cryogenic Techniques.
OTHER METHODS

1. Change of pH/Use Of Buffer


2. Derivatization, Complexation, And Salt Formation
3. Supercritical Fluid Process
4. Use Of Adjuvant Like Surfactant, Solubilizers, Co-solvency,
Hydrotrophy, And Novel Excipients
DRUG PROPERTIES DATA
SOLUBILITY DATA OF COMMON DRUGS
EXPERIMENTAL PROGRESS
SELECTION OF DRUG
After careful consideration of Active Pharmaceutical Ingredient, cost, bio-
availability and solubility, we selected four drugs for experimentation this
semester, viz. Freelex, Spasmonil Plus, Zeldinac SP and Nicip.

Mefenamic
Paracetamol
from Zeldinac SP Acid from
Spasmonil Plus

Magnesium
Nimesulide
Hydroxide from
Freelex from Nicip
EXPERIMENTAL PROCEDURE I
1. In the first step, we powder the
drug using mortar-pestle. Then
we dissolve the powdered drug
in a solvent (ethanol or acetone
have been selected for these
drugs).
2. After dissolving it for about 10-
15 minutes, we filter the
solution. It is heated on hot
plate until crystals appear, and
then a minute quantity of
solvent is added to create a Figure 1: Solution of Figure 2: Solution of
saturated solution of drug in Mefenamic Acid in Mefenamic Acid being
solvent. Acetone filtered.
EXPERIMENTAL PROCEDURE II
1. We put the anti-solvent i.e. water in
the ultra-sonicator machine and add
filtered, saturated drug solution drop
by drop.
2. Sonication of the solution is done to
properly dissolve the medicine
solution in the anti-solvent, and notice
the effect of the ultrasonic
frequencies on the shape of the
precipitate.
3. After sonicating the solution, we keep
the solution at room temp to cool Figure 3: Solution being
down and for the precipitation of the sonicated with anti-
medicine. solvent in ultra-sonicator
EXPERIMENTAL PROCEDURE III
1. After the precipitation of the
medicine, we again filter the
solution and here, the
precipitate is the product
that we desire.
2. After separating the
precipitated drug from the
solution, we dry it and then
go for the XRD Analysis of
the particles of the
precipitate.
3. We shall also do UV Vis
Analysis for bio-availability.
Figure 4: Solution after being
sonicated with developed precipitates
MODIFICATION IN PLAN
TIMELINE

S. No. Task/Segment of Project Estimated Completion Date


1. Finalization of Experimental Procedure March 5, 2018

2. Finalization of Parameters March 20, 2018

3. Preparation of Minor Mid-Review Report March 23, 2018

4. XRD and Micrograph Analysis April 1, 2018

5. Testing by Changes in Other Parameters April 15, 2018

6. Finalization and Compilation of Data May 1, 2018

7. Submission of Final Semester Report and Presentation of Project May 5, 2018


ROUND 2: EXPERIMENTAL PROCEDURE
• As any medicine is a mixture of API and • This solution was then added to 325 ml Pure water,
other supporting components, Round 2 was that acted as Anti-solvent. The drop rate was 3.704 E-3
performed using Pure API to ensure there ml/min. The solution was continuously stirred using
were no other chemical component was
magnetic stirrer.
present. • The mixture was then let to settle for crystallisation.

• In this case the API chosen was • Even after 48 hours, however, no
Paracetamol (Class II). 10ml of Solvent was crystallisation was witnessed
chosen and 2 gm of Paracetamol was
dissolved (in excess).
Solvent Solubility Solvent Volume Amount of
• The mixture was stirred using a magnetic Density taken API
required
stirrer at 400rpm and room temperature for
10 minutes. The solution was then allowed Ethanol 232.75 789 10 ml 1.836 gm
gm/kg kg/cu.m (7.89 gm)
for settling for 2 hours. The clear, saturated
solution was measured to be 8.9 ml.

Table 2: Recorded Data


ROUND 3: EXPERIMENTAL PROCEDURE
• With Round 2 we inferred that the amount
of Anti-solvent (325 ml water) was very
large and could easily accommodate 1.8
gm Paracetamol (Maximum of 4.225 gm The final 18 ml of Saturated Paracetamol-Acetone
can be dissolved in 325ml Water). Solution was then mixed in 50 ml Pure Water at a drop
rate of 3.7 E-3 ml/min. The Water and Acetone Mixture
• So in Round 3, we reduced the Amount of
was then let to settle for 48 hours. However, the solution
Pure Water as an Anti-solvent to 50 ml
showed no crystallisation.
which could accommodate 0.65 gm of
Paracetamol.
• Hence in Round 3, we prepared a 20 ml Solvent Solubility Solvent Volume Amount of
Saturated solution of Paracetamol in Density taken API
Acetone. 1.8 g of API was dissolved in 20 required
ml Acetone using Magnetic Stirrer. The Acetone 111.65 784 kg/cu.m 20 ml 1.75 gm
mixture was let to settle for 2 hours and gm/kg (15.68 gm)
the excess API was filtered out.
Table 3: Recorded Data for Second Run
ROUND 4: EXPERIMENTAL PROCEDURE I
• After Round 2 we could infer that the Within 150 seconds of mixing the Mixture showed clear
solubility of Ani-solvent should be low. To precipitation/crystallisation.
ensure this, we saturated the Water with
Paracetamol. Round 4 proved to be successful and the crystallised
• 50 ml Pure water was mixed with 0.7 gm particles of Pure Paracetamol removed from the mixture
Paracetamol and stirred on Magnetic will be sent for X-Ray Diffraction Analysis and
Mixer at 600 rpm and 40 deg. Celsius Micrograph to observe the differences in Crystallization
and allowed to cool down for 2 hours. after atmospheric drying in the sun.
• The solution with suspended undissolved
API was filtered and the saturated
solution was kept in a beaker. Anti- Solubility Solvent Volume Amount of
Solvent Density taken API required
• A 10 ml Saturated solution was prepared Water 13 gm/kg 1000 50 ml 0.65 gm
similar to Round 1 and mixed with kg/cu.m
Saturated Water Solution with continuous
mixing at 0.4109 ml/min drop rate and Table 4: Recorded Data from third run
600 rpm.
FUTURE PLAN

• Having identified a preliminary method for Crystallisation using Anti Solvent, our
next steps will involve the following:
• Effects of Drop-rate, Agitation/Mixing, Solvent/Anti-Solvent Ratio, on Crystallization. We
identify this using different Drop-rate and Rotation velocity of Magnetic Stirrer.
• Micrograph, X-Ray Diffraction, FTIR, SEM, Bioavailability Tests, depending upon the
feasibility to identify the changes in Crystal Structure, Surface Characteristics,
Bioavailability, etc.

• This will lead to conclusion of experiment after factoring in the effect of multiple
variables and process streamlining vis a vis the most effective experimentation
methodology.
EXPERIMENTAL PHOTOS
SUMMARY
 The oral bioavailability of BCS (biopharmaceutical classification system)
class II drugs with poor solubility and reasonable permeability is limited
by the drug dissolution step from drug products.
 General parameters affecting solubility are particle size, shape and
surface area physicochemical properties of drugs, physical forms of
drugs, solvents, pH of the medium, temperature and use of surfactants.
 In this Project, pharmaceutical particle technology is employed to
improve poor aqueous solubility of drug compounds that
limits in vivo bioavailability owing to their low dissolution rate in the
gastrointestinal fluids following oral administration.
 By surface enhancements, the drugs considered will be made available
for ingestion, saving costs and other resources used in injection, and
providing a quicker and more effective treatment path.
REFERENCES
Plagiarism is Criminal.
REFERENCES
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• “Drug Bioavailability: Estimation of Solubility, Permeability, Absorption and Bioavailability (Methods and Principles in Medicinal
Chemistry)”, Folkers G, van de Waterbeemd H, Lennernäs H, Artursson P, Mannhold R, Kubinyi H (2003).

• “Biopharmaceutics Classification System (BCS): Development, Implementation, and Growth”, Mehta M (2016).

• Charkoftaki, G., Dokoumetzidis, A., Valsami, G. and Macheras, P. (2010), “Biopharmaceutical Classification Based on Solubility and
Dissolution: A Reappraisal of Criteria for Hypothesis Models in the Light of the Experimental Observations”. Basic & Clinical
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