This document describes the development and characterization of hydrogel microparticles containing lovastatin for the purpose of enhancing its solubility and bioavailability. Lovastatin is a poorly water soluble drug with low oral bioavailability. β-cyclodextrin and 2-acrylamido-2-methylpropane sulfonic acid (AMPS) were used to synthesize poly(β-CD-g-AMPS) hydrogel microparticles via free radical polymerization. Various formulations with different ratios of β-CD, AMPS, crosslinker and initiator were prepared and tested for drug entrapment efficiency, particle size, swelling, and in vitro drug release. The lovastatin loaded microparticles showed up to 9.37

1. Development, Optimization and Characterization of
Hydrogel Microparticulate System for solubility
enhancement of Lovastatin

2. Hydrogels
Hydrogels are three dimensional hydrophilic polymeric networks
having ability to imbibe large amounts of water and other biological
fluids.
When these are structured into micrometric scale these are referred as
Hydrogel microparticles.
Water pulling inside the polymeric matrix depends upon presence of
functional groups (governed by reactive polymers and monomers),
capillary action and osmotic pressure variability.

3. Functional groups that impart hydrophilicity to the developed
networks include –NH2, –COOH, –OH, –CONH2, –CONH, and –SO3H.
β-Cyclodextrin, a truncated cone having hydrophobic cavity and
hydrophilic outer rim. β-CD is listed in generally regarded as
safe list of US FDA.
Cyclodextrins when incorporated into polymeric networks their
ability to enhance solubility and bioavailability is potentiated.
2- Acrylamido -2- methylpropane sulfonic Acid (AMPS) is a white
crystalline powder having hydrophilic nature but poor
solubility in organic liquids.

4. Swellability of AMPS is highly dependent on ionizable
sulfonate groups. AMPS containing products detach over all
pH range thus confirming pH independent swelling.
Different techniques are available in literature for solubility
enhancement i.e. kneading, solvent evaporation,
solubilization, salt formation, RDT’s, microemulsions,
prodrug formation, hydrosols, micronization, IPNs, hydrogel
microparticles etc.

5. Lovastatin
Lovastatin is a cholesterol-lowering agent which is widely used to
treat hypercholesterolemia. It belongs to BCS class II. Lovastatin
exhibits poor oral bioavailability of <5% because of its low
aqueous solubility and extensive metabolism in the gut and liver.
Figure: Chemical structure of Lovastatin

6. Physico-chemical properties of Lovastatin
 White to light yellowish crystalline powder.
 Half-life is 2 – 5 hrs.
 It presents poor oral bioavailability i.e. <5%.
Solubility profile
 Freely soluble = Chloroform
Soluble = Dimethyl formamide
Poorly soluble = Water i.e. 0.0004 mg/ml.

8. Drug carrier system was developed keeping in view the following
Objectives:
1. To develop and characterize Lovastatin loaded hydrogel
microparticles.
2. Solubility and bioavailability enhancement will cut short
wastage of active chemical moieties.
3. To reduce overall cost of the therapy.
4. To reduce Lovastatin associated toxic effects.
5. To improve patient compliance and comfort.
Study Objectives

9. Materials
 Lovastatin
 β- Cyclodextrin
 2- Acrylamido -2- methylpropane sulfonic Acid (AMPS)
Potassium persulfate
 N, N – Methylene bisacrylamide
 Methanol
 Potassium dihydrogen phosphate
 Hydrochloric acid
 Orthophosphoric acid

10. Composition of poly(β-CD-g-AMPS) Hydrogel
Microparticles
Code
β-Cyclodextrin
(g/100g)
AMPS
(g/100g)
MBA
(g/100g)
APS
(g/100g)
BA-1 0.5 2 0.3 0.1
BA-2 1 2 0.3 0.1
BA-3 2 2 0.3 0.1
BA-4 1 4 0.3 0.1
BA-5 1 5 0.3 0.1
BA-6 1 6 0.3 0.1
BA-7 1 4 0.4 0.1
BA-8 1 4 0.5 0.1
BA-9 1 4 0.6 0.1

11. β-Cyclodextrin-g-2-Acrylamido-2-methylpropane
sulfonic
acid (AMPS) Hydrogel Microparticlesβ-cyclodextrin was dissolved
in water on aluminium hot
plate magnetic stirrer (75°C)
until clear solution was
formed
AMPS was separately added
in water on aluminium hot
plate magnetic stirrer (40°C)
until clear solution was
formed
Solution
1
KPS
MB
A Solution
2Solution 2 was added
dropwise into Solution 1
S1 +
S2
Purged with nitrogen gas (20
mins)
Whole mixture was poured into glass
moulds
Gelling (65°C,
12h)
Cutting &
Washing
Lyophilization &
Sieving
Hydrogel
microparticle
s

12. Formulations
% Entrapment
efficiency
Product yield (%)
BA-1 88.90 ± 1.50 84.10 ± 0.20
BA-2 87.60 ± 0.15 85.00 ± 1.50
BA-3 88.80 ± 0.50 86.20 ± 0.30
BA-4 90.00 ± 1.15 87.00 ± 0.25
BA-5 88.90 ± 0.25 86.20 ± 0.15
BA-6 86.90 ± 0.30 87.90 ± 0.20
BA-7 90.00 ± 1.50 86.70 ± 0.30
BA-8 89.80 ± 0.20 88.00 ± 0.20
BA-9 87.90 ± 0.50 87.10 ± 0.50
Entrapment efficiency and Product yield
*Mean ± Standard Deviation (SD), n = 3.

13. Micromeritic properties
Code
Bulk
density
(g/ml)
Tapped
density
(g/ml)
Angle of
repose
(ϴ)
Hausner’s
Ratio
Carr’s
index
(%)
BA-1 0.786 0.922 24.50 1.17 14.75
BA-2 0.791 0.940 23.70 1.18 15.85
BA-3 0.799 0.947 22.65 1.18 15.62
BA-4 0.823 0.968 23.40 1.17 14.97
BA-5 0.789 0.927 25.80 1.16 14.88
BA-6 0.796 0.931 22.25 1.16 14.05
BA-7 0.812 0.937 23.50 1.15 13.34
BA-8 0.785 0.929 25.70 1.18 15.50
BA-9 0.793 0.941 23.10 1.18 15.72

14. FTIR studies
β-Cyclodextrin
Lovastatin
-OH
-C-O
-CH -C-O

15. FTIR spectra of AMPSA

16. FTIR spectra of β-CD-g-poly (AMPS)

17. 000000000000000000000000000000000000000000 0 0 0 0
29.556
53.102
17.342
0 0 0 0 0 0 0 0 0 00
10
20
30
40
50
60
0 200 400 600 800 1000 1200 1400 1600 1800 2000
Volume(%)
Particle size (μm)
Particle size determination
Optical Microscopy
Optical microscope (Nikon E200, Tokyo, Japan)

18. DSC Spectra of β-CD-g-poly (AMPS)
211.69°C
199.12°C
0.01275J/g 325.24°C
314.66°C
0.006885J/g
0.000
0.005
0.010
0.015
0.020
HeatFlow(W/g)
0 50 100 150 200 250 300 350 400
Temperature (°C)
Sample: H A
Size: 2.4570 mg
Comment: H A
DSC-TGA
File: D:TGARAYH A.001
Run Date: 18-Apr-2015 08:25
Instrument: SDT Q600 V8.2 Build 100
Exo Up Universal V4.2E TA Instruments

19. TGA thermogram of β-CD-g-poly (AMPS)
9.00min
213.71°C
79.81%
14.70min
327.46°C
54.23%
20
40
60
80
100
Weight(%)
0 50 100 150 200 250 300 350 400
Temperature (°C)
Sample: H A
Size: 2.4570 mg
Comment: H A
DSC-TGA
File: D:TGARAYH A.001
Run Date: 18-Apr-2015 08:25
Instrument: SDT Q600 V8.2 Build 100
Universal V4.2E TA Instruments
β-CD = 273.76 °C
Lovastatin = 174.5 °C

20. XRD Studies
Physical Mixture
β-CD-g-poly (AMPS)
Lovastatin

21. SEM micrographs of (β-CD – g – AMPS) Hydrogel Microparticles

22. pH 1.2 = 5.70 folds, pH 7.4 = 8.09 folds and Water = 9.37folds
Solubility
studies
0.85
2.01
0.4
4.85
16.2754
3.75
0
2
4
6
8
10
12
14
16
18
pH 1.2 pH 7.4 Water
LVTSolubility(µg/ml)
LVT LVT Hydrogel
microparticles

23. Swelling studies
Tea Bag Method
(Mahdavina et al., 2004)
0
20
40
60
80
100
120
0 50 100 150 200
Equilibriumswelling(%)
Time (min)
pH 7.4
pH 1.2

24. Kinetic Models
Kinetic
Models
pH 1.2 pH 7.4
Zero order
Parameters
BA-1 to BA-9
(Mean)
BA-1 to BA-
9 (Mean)
R2
0.8189 0.8241
T25 39.176 40.077
T50 78.353 80.154
T75 117.529 120.230
First order
R2
0.9934 0.9874
T25
17.093 18.335
T50 41.185 44.176
T75 82.370 88.351
Higuchi R2
0.9336 0.9460
Korsmeye
r Peppas
R2
0.9494 0.9577
N 0.419 0.748

25. Conclusions
From results of prepared formulations it was concluded
that solubility of Lovastatin was enhanced.
Hydrogel microparticles containing β-CD and AMPS as
polymeric unit potentiated solubility of Lovastatin upto
5.70 and 8.09 folds at pH 1.2 and 7.4, respectively.
Hydrogel microparticles prepared by free radical
polymerization can be used an effective tool for
solubility enhancement of other hydrophobic drugs.

26. Acknowledgements
Higher Education Commission (HEC) of Pakistan

27. Related Publications
 Asif Mahmood, Mahmood Ahmad, Rai Muhammad
Sarfraz & Muhammad Usman Minhas. β-CD based
hydrogel microparticulate system to improve the solubility
of acyclovir: Optimization through in-vitro, in-vivo and
toxicological evaluation. Journal of Drug Delivery
Science and Technology, 2016;36:75-88.
 Asif Mahmood, Mahmood Ahmad, Rai Muhammad
Sarfraz & Muhammad Usman Minhas. Development of
Acyclovir Loaded β-Cyclodextrin-g-Poly Methacrylic Acid
Hydrogel Microparticles: An In Vitro Characterization.
Advances in Polymer Technology, 2016. DOI
10.1002/adv.21711.
 Asif Mahmood, Mahmood Ahmad, Rai M. Sarfraz,
Muhammad U. Minhas & Ayesha Yaqoob. Formulation and
In-Vitro Evaluation of Acyclovir Loaded Polymeric
Microparticles: A Solubility Enhancement Study. Acta
Poloniae Pharmaceutica – Drug Research, 2016;73(5):
1311 -1324.

28.  Rai M. Sarfraz, Mahmood Ahmad, Asif Mahmood,
Muhammad U. Minhas & Ayesha Yaqoob. Development
and Evaluation of Rosuvastatin Calcium Based
Microparticles for Solubility Enhancement: An In Vitro
Study. Advances in Polymer Technology, 2015. DOI
10.1002/adv.21625.
 Sarfraz, Rai Muhammad, Mahmood Ahmad, Asif
Mahmood, and Hira Ijaz. "Development, In Vitro and In
Vivo Evaluation of pH Responsive β-CD-Co methacrylic
Acid-Crosslinked Polymeric Microparticulate System for
Solubility Enhancement of Rosuvastatin
Calcium." Polymer-Plastics Technology and
Engineering (2017): 1-13.
 Sarfraz, Rai Muhammad, Mahmood Ahmad, Asif
Mahmood, Muhammad Rouf Akram, and Asad Abrar.
"Development of β-cyclodextrin-based hydrogel
microparticles for solubility enhancement of rosuvastatin:

29. Thanks for
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