PHARMACEUTICS

Methods to enhance solubility of poorly

soluble Glimepiride drug

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 Glimepiride

Glimepiride is an anti-diabetic medication that belongs to the third generation of

sulfonylureas. It belongs to class II and is distinguished by its poor solubility and high
permeability.

Method 1: Development and Characterization of Glimepiride Novel Solid dispersion

for Improving Its Oral Bioavailability

Objective

To manufacture glimepiride as a solid dispersion with water-soluble carriers in order to

improve its aqueous solubility and hence its bioavailability.

Materials

Glimepiride, PEG 6000, β-cyclodextrin, Mannitol and Methanol.

The Preparation of GM Solid Dispersion

Solid dispersion is a well-established approach for increasing the aqueous solubility of

pharmaceuticals that are weakly water-soluble. The weakly water-soluble medicines are
disseminated through a water-soluble carrier such as urea, mannitol, polyethylene glycol,
polyvinyl pyrrolidone, and -cyclodextrin in this approach. Melting, solvent evaporation,
and spray drying processes are used in the process of solid dispersion.

The GM solid dispersion formulations were made utilizing the solvent evaporation
technique with three distinct carriers (mannitol, polyethylene glycol (PEG) 6000, and
-cyclodextrin) and three different drug carrier ratios (1:1, 1:3, and 1:6). The carrier’s
mannitol, PEG 6000, and beta-cyclodextrin were chosen based on the findings that they
were successful in improving the solubility of weakly water-soluble medicines. In a
round-bottomed flask, weighed quantities of GM and carriers were dissolved in 10 mL of
methanol. The solvent was allowed to evaporate in a Heidolph rotavap , which was
rotating until fully dry. The solid dispersion of GM on the wall of a round-bottomed
flask was left after the methanol was evaporated . The produced GM solid dispersions
were harvested and oven dried at and stored in a desiccator over silica at relative
humidity at room temperature for future experiments.

To choose the optimal formulation, the produced formulation was examined for
production yield, drug content, micrometric characteristics, and in-vitro release research.

The Drug Content %(DC%)

The drug content of all GM solid dispersion formulations was determined. The high drug
content value suggested that the carriers and technique of preparation were reliable.
These findings were obtained after preparing the GM solid dispersion with PEG 6000 and
discovering that the drug concentration was in the 97.5 percent range.

The In-Vitro Release Study of GM From Solid Dispersion

According to the findings of the in-vitro release, as shown in Figure , the release for all
formulations varied from 65.17 percent for F4 to 99.9 percent for F9. Furthermore, the
release from all formulations was much greater than the release of free drug, indicating
that the solid dispersion approach has the capacity to improve the GM's dissolving rate.
This might be ascribed to the drug being converted into a more soluble amorphous state,
and lowering the interfacial tension between the GM and the dissolving media resulting
in improved wettability and drug dissolution.
  Figure : The in-vitro release of glimepiride from all developed solid dispersion
formulations and pure medication was investigated.

Result and discussion

It was observed that the release differed depending on the carrier (B - cyclodextrin >
Mannitol > PEG 6000). The variation in the hydrophilic impact of the carriers may
account for these findings. Furthermore, raising the drug carrier ratio from 1:1 to 1:6
enhanced release for each carrier, which might be attributable to increased wettability and
surface area as the fraction of water-soluble carriers increased.

Conclusion

high and rapid reduction in blood glucose levels in diabetic rats, which indicated the
success of a solid dispersion technique in improving the solubility and hence the
bioavailability of glimepiride.

Method 2 : Dissolution of Glimepiride−Captisol Inclusion Complexes .

Objective

Captisol , a chemically modified cyclodextrin, was tested for its influence on glimepiride
in vitro solubility.

Captisol Enhances Water Solubility of Glimepiride

Cyclodextrins are well-known cavitands because they encapsulate poorly water-soluble

medicines within their hydrophobic chamber and improve water solubility through their
hydrophilic surface.
Materials :

Glimepiride and Captisol

Preparation of Physical Glimepiride-Captisol Mixtures

Triturating for 30 minutes with a mortar and pestle blended and homogenized different
mass ratios of glimepiride and Captisol.

Preparation of Inclusion Complexes of Glimepiride and Captisol

Using Freeze-Drying, Inclusion Complexes of Glimepiride and Captisol are Prepared.

The inclusion complexes were created by dissolving glimepiride and Captisol in water in
varying mass ratios to create a homogenous mixture. Initially, weighted glimepiride was
added to water and swirled, followed by weighted Captisol, which was added to the
solution and stirred for 24 hours using a magnetic stirrer. The solution was filtered, and
the filtrate was freeze-dried at 40 °C for 12 hours, yielding a dry powder.
Glimepiride/Captisol physical mixture (μg/ml) inclusion complex(μg/ml)

1:1 0.34 0.43

1:2 0.40 1.03

1:3 0.59 1.94

Result and discussion

Water solubility of these preparation compared to that of the pure drug to derive a
solubility enhancement factor, which is the ratio of the amount of glimepiride that
dissolves in distilled water from the physical mixture or inclusion complex to that of the
pure drug. The enhancement factor rises in distilled water, demonstrating that Captisol
improves glimepiride's water solubility. Furthermore, glimepiride solubility rises with
mass ratio, as a 1:3 ratio resulted in a more than one-fold increase in enhancement factor.
We discovered that increasing the quantity of Captisol in a physical mixture or inclusion
complex enhances drug solubility in distilled water, and that the enhancement factor of
inclusion complexes was higher than that of physical mixes.

Glimepiride interacts with Captisol, according to solid-state analyses.

We found drug residues on the surface of the physical mixture, as opposed to the
inclusion complex, which had none most likely due to encapsulation with the
hydrophobic core. The glimepiride PXRD diffract gram was crisp and strong, supporting
the drug's predicted crystallinity, but Captisol's was wide, indicating amorphousness.

Conclusion

Indeed, in vitro dissolution assays reveal that glimepiride's water solubility in the
physical combination and inclusion complex is greater than that of the pure medication.
Overall, our findings indicate that Captisol can increase the water solubility of
hydrophobic medicines, hence increasing their bioavailability.
References

 Qushawy M, Nasr A, Swidan S, Mortagi Y. Development and Characterization of

Glimepiride Novel Solid Nanodispersion for Improving Its Oral
Bioavailability. Scientia Pharmaceutica. 2020; 88(4):52.

 Pal, A., Roy, S., Kumar, A., Mahmood, S., Khodapanah, N., Thomas, S.,
Agatemor, C., & Ghosal, K. (2020). Physicochemical Characterization, Molecular
Docking, and In Vitro Dissolution of Glimepiride-Captisol Inclusion
Complexes. ACS omega, 5(32), 19968–19977.
https://doi.org/10.1021/acsomega.0c01228