Beny Baby et al /J. Pharm. Sci. & Res. Vol.

13(1), 2021, 64-69

Preparation and evaluation of oral liquid sustained delivery

of Metformin HCl
Beny Baby*, B.Prakash Rao
Department of Pharmaceutics, Karnataka College of Pharmacy, Bangalore 560064

Abstract
Aims: The aim of the work was to develop an oral liquid sustained delivery form of Metformin HCI (MH) by a simple
processing method at low cost. The Primary objective of this system is to ensure safety and to improve efficacy of the drugs
as well as patient compliance. This is achieved by better control of plasma drug levels and less frequent dosing. This drug
delivery is highly appreciable for geriatric and pediatric patients.
Methods: A Preliminary Research was carried out for the development of oral liquid sustained delivery of Metformin HCl.
Various batches of formulations have been developed with varying concentrations of chitosan. The cumulative drug release
from optimized formulation was compared with the marketed formulation.
Results: The Oral Liquid Sustained Delivery of Metformin HCl is almost effective like of Conventional Metformin tablets in
terms of bioavailability and less toxicity.
Conclusion: The experimental oral liquid loaded Metformin HCl have shown improved efficacy in comparison with
conventional Metformin tablets. The invitro studies revealed the success of drug release in a sustained manner.
Key words: Conventional Dosage Forms, Metformin HCl, Oral Liquid, Polymer Dispersion,Sustained delivery, Type-II diabetes.

INTRODUCTION: concept of controlled release drug delivery can be

Diabetes mellitus is considered as a chronic metabolic employed for the formulation of Metformin HCl [7]. The
disorder which is identified by high blood glucose level controlled release dosage form which is appropriately
caused by insulin deficiency or due to insulin resistance. designed is immensely helpful to gain therapeutic efficacy
Apart from regular exercise and balance diet, various and safety to the patients. To ensure safety and to improve
hypoglycemic drugs involve to adequately controlling the effectiveness of the drugs, controlled/sustained release
blood glucose level [1]. Diabetes is a gathering of metabolic dosage form is designed [8]. The concept of different
maladies caused from imperfect insulin emission or its dosage forms like controlled release tablet [9], floating
activity or both coming about hyperglycemia. Insulin is the tablet [10], osmotic pump tablet [11], microspheres [12],
hormone emitted by pancreas and delivered in blood. The beads [13] etc. are put forwarded to regulate the release as
guideline of glucose from blood in body cell is finished by well as to increase the effectiveness of the drug. Among the
insulin [2]. Pathogenic cycles engaged with advancement various approaches for controlling the drug release, liquid
of diabetes may run from immune system devastation of β- oral sustained release formulation would be the best
cells of pancreas to a few irregularities coming about approach in this regard. Various approaches like sustained
protection from insulin. The anomaly in starch, protein and release coated microparticles and in situ gelling system are
fat digestion is described by lacking insulin movement. highly implemented in the oral delivery of liquid
Metformin HCl [MH] is orally administered biguanides formulation for controlled/sustained release of the
antihyperglycemic drugs used in the preferential treatment pharmaceutical ingredients. The application of ion
of type-2 diabetes [3]. Metformin typically induces exchange like alginates along with chitosan on the oral
adenosine monophosphate-activated protein kinase in the liquid formulation results on the formation of gel in the
liver, resulting hepatic uptake of glucose and reducing stomach as well as in the stomach [14].
gluconeogenesis through complex effects on the The demand of oral liquid sustained medication conveyance
mitochondrial enzymes. The hepatic and peripheral tissue frame works in diabetes has demonstrated better
sensitivity of insulin was improved tremendously with the conveyance of little atom drugs which may expand the
effective use of Metformin HCl. It is hydrophilic in nature personal satisfaction in diabetic patients. Ordinary dosage
and incompletely absorbed form Gastro intestinal type of enemies of diabetics display variety in the
membrane. Therefore, it was reported that the absolute bioavailability and shorter half life prompting incessant
bioavailability of 500 mg tablet was only 50-60% [4]. As dosing consequently expanding the symptoms prompting
Metformin HCl shows high aqueous solubility and low less helpful impact. Considering the states of the diabetes
intestinal permeability, it is classified under the BCS class continued medication conveyance-based methodologies are
III of Bio Pharmaceutics Classification System [5]. all the more encouraging as far as giving better viability
It was reported that, conventional Metformin HCl tablets delivery [15].
were used for the treatment of type 2 diabetes. The plasma The tablet and capsules must be gulped down as an entire
elimination half life of Metformin HCl is relatively short unit and in the event of dose modification, these can't be
i.e. 1.5 to 4.5 hours [6]. Consequently, to achieve broken into equal parts as they are intended for controlled
therapeutic efficacy, it is administered 2 to 3 times in a day. delivery and the gliding capacity additionally relies upon
The increase in dosing frequency may decrease the patience measurements of the tablet. Old and dysphagic patients
compliance. Therefore, to rectify such problems, the think that it’s hard to swallow massive tablets and cases. In

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such cases, high dosages of the medication can be Methods:

consolidated into Liquid oral [16, 17]. Pre-formulation studies:
The biodegradable polymers can give a further authority Drug-excipient compatibility studies by FT-IR
over medication discharge rates and stays away from the To investigate any possible interaction between the drug
issues identified with the evacuation of the conveyance and polymers used, the IR spectrum of the pure drug (MH)
gadget after medication consumption [18]. Chitosan is a and the binary mixture of drug and polymers was taken using
cationic, biocompatible, and biodegradable regular FTIR (UV visible spectrophotometer, Alpha Bruker) [33-
polymer, acquired by antacid deacetylation of chitin. It is a 35].
widely contemplated biomaterial in the field of
medication/quality conveyance, tissue designing, and food Design of experiment and statistical optimization
innovation. Because of mucoadhesive property, chitosan The regular strategies for experimentation by transforming
nanoparticles can improve oral bioavailability of each factor in turn being tedious, the Design of Experiment
medications because of their expanded living arrangement (DOE) was finished utilizing the JMP Statistical Software
time inside the gastrointestinal parcel and expanded contact (Trial variant 13). The polymers and different amounts were
time with the intestinal epithelium cells, accordingly chosen dependent on announced writing on comparative
expanding their take-up. investigations and starting screening tests done to
Different normal and engineered polymers including distinguish the ideal conditions and amounts required.
polysaccharides like carrageenan, gellan gum, gelatin and Assessment of primer groups was done dependent on
sodium alginate have been utilized in the advancement reactions, for example, in vitro release considers, drug
experiences a stage progress in nearness of different di and delivery and pourability (relative consistency), to choose
trivalent particles [19-21]. Sodium alginate is a the working focus scope of polymers (factors).
characteristic and hydrophilic polymer reasonable for the
entanglement of water-solvent medications [22-24] broadly Formulation of Oral Liquid Metformin HCl by Polymer
utilized in pharmaceutical details [25-27]. HPMC is utilized Dispersion Method
as a consistency modifier. Sorbitol is utilized as a sugar in Metformin HCl was prepared by Polymer dispersion
liquid orals and studies have indicated that gels containing method. An accurate amount of Metformin hydrochloride
10-17 % Sorbitol continued the arrival of medication in dissolved in 5 mL of water using sonicator for 5 mins for
rodent stomach and a bioavailability of roughly 90% was complete solubility. Now, specified amount of chitosan
accomplished from orally directed syrups [28-30]. (Table 1) were dispersed in aqueous solution of glacial
The constraints related with the traditional structures acetic acid and stirred by magnetic stirrer for 1 h. The
require the advancement of novel details that can convey aqueous solution of drug is poured slowly into the aqueous
the medication straightforwardly at a diminished dosing solution of glacial acetic acid containing chitosan with
recurrence. Among the transporters for supported delivery, continuous stirring and 20 mg of sodium benzoate is
polymeric particles, liposomes and strong lipid dissolved in 2.5 mL of water which is used as preservative
nanoparticles (SLNs) have been used to embodied for and transferred to the formulation with continuous stirring
controlling release [31]. Considering the way that Oral for 1h at 600 rpm and 10 mg of Sodium Trioly Phosphate
Liquid Sustained Delivery of Metformin has great dissolved in 2.5 mL of water and transfer to the formulation.
biocompatibility, great security and the property to expand
tranquilize discharge [32]. Polymeric Suspensions may be Evaluation:
used as a transporter for the exemplification and continued pH of the Formulation:
conveyance of Metformin HCl. Along these lines, in the The pH of the formulation was determined using a
current examination, the primary goal was to detail calibrated pH meter and readings taken in triplicate [36, 37].
Metformin HCl in the type of oral liquid Sustained Delivery
and to assess its in vitro exhibition and in vivo Studies. Viscosity:
The research work focused on the turn of events and The thickness of the solution was resolved utilizing
assessment of a coasting, oral liquid measurement type of Brookfield viscometer (DV-II+ Pro LV model). The choose
Metformin HCl for continued delivery, alongside giving plans (250 mL) were filled the example connector of the
proof seeing tweaked sedate delivery according to viscometer and the consistency estimated at room
legitimate details. No oral liquid supported delivery plans temperature utilizing SC4-18 axle for the solutions. The
of Metformin HCl are accessible in market on today and precise speed was step by step expanded from 10 to 50 rpm
consequently an endeavor is being to build up the with a 6 sec pause period, the chain of command turned
equivalent. around and the normal taken. The consistency estimations
were made in triplicate [38].
MATERIALS AND METHODS
Materials: Determination of Drug Content:
Metformin HCl, Chitosan, Calcium carbonate, Sodium Around 50 mg of Metformin Hydrochloride identical to Oral
Benzoate, Sodium TriPolyphosphate, Sodium Citrate were Liquid Suspension was dissolved in 50 mL of water and
obtained from Yarrow Chem Products, Mumbai. sonicated for 45 minutes. At that point 10 mL of the above
arrangement was diluted to 100 mL with water. 1 mL from
the above arrangement was taken and diluted to 10 mL with

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water and estimated at 232 nm under UV soundness with regard to physical appearance, drug
spectrophotometer and the level of medication content was substance and drug release attributes in the wake of putting
determined. away in a stability chamber (Thermolab) at 40 °C/75% (RH)
for 6 months. The product was filled in a HDPE bottle with
In vitro drug release and kinetics: sealed CRC caps [47, 48].
The drug release study was completed utilizing USP Type
II dissolution device (Paddle type, Electrolab). 1 mL of the RESULTS AND DISCUSSION:
definition equal to 500 mg/mL was kept in Dialysis Preformulation study:
Membrane and dissolution done. At predetermined time Drug-excipient compatibility studies by FT-IR:
stretches, 1 mL of test arrangement was withdrawn, No critical movements or decrease in the force of the FTIR
separated through a 0.45μm membrane, reasonably diluted groups of MH were seen as illustrated in the Figure 1.These
and analysed by UV spectrophotometrically at 232 nm. A groups were additionally watched for the physical blend of
similar measure of new dissolution medium was supplanted polymers alongside MH, in this manner affirming that there
following withdrawal of the test [39-41]. The system of was no interaction between MH, polymers and excipients
drug was concentrated by fitting the dissolution information utilized and that they were viable with the drug.
in the zero-request, first-request, Higuchi model and
Korsmeyer-Peppas condition following model-subordinate Metformin HCl liquid Oral Sustained Formulation:
energy. Based on the slope and r2 Optimization values In this research work, formulations were prepared in which
obtained, the mechanism of drug release was determined Chitosan were used as drug carrier. The chitosan is used as
[42-45]. coating agent to the pure drug in order to reduce impact on
their body and increase their bioavailability.
Optimization:
The qualities got in the wake of assessing the reactions In vitro Drug Release Studies:
tentatively were taken care of into the JMP programming The in vitro drug release studies for the Metformin HCl
and the information examined. The mathematical formulation and optimized formulae were done and the
enhancement methods and the least square fit model were results compared with the marketed conventional dosage
utilized. The attractive quality methodology (utilizing forms (Table 4). The drug release data fitted into the various
Prediction profiler) was used to produce the ideal settings models showed very close r2 values (above 0.8).
for the plan. Advancement was accomplished for the The r2 values of the Higuchi model of all the formulations
reactions by keeping drug release at 1h at most extreme showed higher values indicating that the drug release was
while that at 8 h and 12 h were kept in the range [46]. The directly proportional to square root of time. But n values
advancement target and limitations were set dependent on ranging from 0.2033 to 0.5239 indicated Fickian diffusion
the official IP details. mechanism. It may be coincident. However, n values of
Korsmeyer-Peppas strongly indicated Fickian diffusion.
Statistical Analysis:
Statistical analysis was carried out using the ANOVA and Stability studies:
p-values less than 0.05 were considered statistically Stability studies carried out on the optimized formulation as
significant. per ICH guidelines (Q1C) revealed no significant changes in
the physicochemical properties, viscosity or drug release of
Stability Studies: the formulation even on the aging of the liquid orals under
Accelerated stability studies were directed according to the different storage conditions.
ICH Q1C rules on the streamlined detailing to survey the

Table 1: Composition of Oral Liquid Metformin HCl by Polymer Dispersion Method

Formulation Drug (mg) Drug: Chitosan Sodium Sodium TPP Cold water Glacial acetic Acid
Code Benzoate (mg) (mL) (mL)
(mg)
R1 400 100:100 20 10 10 70
R2 300 200:400 20 10 10 70
R3 400 100:200 20 10 10 70
R4 300 200:200 20 10 10 70

Table 2: Optimized formula (R5) of Metformin HCl suspension by DOE

S.No Ingredients Quantity(mg)
1 Metformin Hydrochloride 382.5
2 Chitosan: Drug 221.88:178.12
3 Sodium tri-polyphosphate 20
4 Sodium benzoate 10
5 Cold water 5 mL
6 Glacial acetic acid (1%) 1

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Table 3: Response variables of the various batches of formulations

Viscosity Entrapment
Formulation Code pH Drug Content (%) In vitro Release (%) (12 h)
(Cps) efficiency
R1 7.1 420 91.25 87.15 92.03
R2 6.9 390 89.20 85 86.61
R3 6.8 540 84.20 82.5 83.91
R4 7.1 380 80.50 83 81.20
R5 7.2 400 91.25 87.15 92.03
*R5 is optimized formulation

Table 4: Comparison of drug release profile of optimized formula(R5) with marketed product
Time(h) %CDR (Optimized Formula-R5) %CDR (Marketed Product) IP specifications
0 0 0
Not less than 25% and not more than
1 39.248 42.366
50% in 1 hour
2 50.075 51.251
3 67.669 69.336
4 70.376 72.001
5 73.083 74.456
Not less than 45% and not more than
6 75.789 77.123
75% in 3 hours
7 78.496 79.821
8 83.910 84.125
9 86.617 85.125
10 92.030 95.123 Not less than 80%.

Figure 1: FT-IR peaks illustrating the compatibility of Metformin with Excipients

100
90
80
70
60
CDR %

50
40 CDR % of optimized formulae
30
20 CDR % of marketed formulae
10
0
0 2 4 6 8 10 12
Time(h)
Figure 2: Comparison of CDR % of Optimized formula (R5) with Marketed Dosage Form

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