Controlled Release of an OTC Cough Suppressant in a Soft Gelatin Based Dosage Form
Haley Pulito, Jaydip Vasoya, Saujanya Gosangari
haley.pulito@thermofisher.com | jaydip.vasoya@thermofisher.com | saujanya.gosangari@thermofisher.com

Thermo Fisher Scientific

PURPOSEThe purpose of the present study was to design a controlled release soft gel capsule based drugdelivery system for a model cough suppressant drug. Soft gel capsule is a very commonly available
dosage form for various medications as it offers several advantages like delivering liquid and lipid (oil)based medications, taste masking, aesthetic appearance and many more. However, manufacturing ofsoft gel capsules is often limited by high viscosity of liquid fill and higher temperatures needed toencapsulate these viscous fills. Purpose of this study was to show a formulation approach leading toselection of a fill material which is amenable to easy encapsulation process while retaining desired
controlled release characteristics from capsules.

RESULT(S) Fill formulations based on hydrophilic and hydrophobic vehicles mixed with wax/polymers andtheir characterization for encapsulation and drug release.

Evaluation offormulation
Melt temperature/Homogenization

Oil based vehicle

Hydrophilic vehicle

Compritol 888 based Gel oil basedfill
formulation

PEO based fill

PEO/Povidone Based fill

Clear liquid above
70˚C

Flowable. Homogenized
at 50˚C

Flowable. Homogenized at50˚C

Flowable at room
temperature

Flowable at room
temperature

Clear liquid at temp
>60˚CFill flowability below Solidifies below 50˚C Flowable at 40˚C40˚COBJECTIVE(S)Objective of this study was to screen various hydrophobic and hydrophilic waxes and polymers withcontrolled release technology (Versatrol) to formulate a model cough suppressant drug. Two
approaches were explored using a proprietary controlled release technology (Versatrol): hydrophiliccarrier-polymer based matrix and lipophilic carrier-high melting wax matrix. Several polymers andwaxes were also explored in combination to achieve extended release of the drug and easy
encapsulation process.

Drug release

Incomplete drug
release due toinsoluble lipids

Incomplete drug release Complete drug release.
due to insoluble lipids
Variable release withdifferent PEO
concentrationsEncapsulation

Difficult/Not feasible Feasible at 40˚C

Feasible at room
temperature- Fill became viscousafter 24 hours

Complete drug release.
Variable release withdifferent PE/Povidone
concentrations
Feasible at room
temperature- Fill became viscous after 24hours-difficult encapsulation

Drug release from hydrophobic vehicle containing wax

Preparation of fill formulations:
Polymers and/or wax were mixed with a suitable vehicle to form binary/tertiary mixtures. These
mixtures were heated or homogenized to obtain a homogenous mixture in hot air oven or
homogenizer, respectively. The mixtures were homogenized when heating was not needed (e.g. incase of polymeric excipients in vehicle) while the mixtures were heated when heat was necessary toobtain homogeneous mixture (e.g. melting of wax with lipid vehicle). After obtaining homogeneous
mixtures, they were cooled to room temperature before adding the API in the mixture. After adding
the API, the mixtures were homogenized using handheld homogenizer.
Evaluation of capsule fill formulations
Formulations were characterized for sedimentation rate, flowability and viscosity. Fills manufactured
with two different approaches were also evaluated for the impact of hold time on physical properties
and encapsulation. For preliminary evaluations, fill was dispensed into two-piece capsules fordissolution performance evaluation. The lead candidates from both approaches were encapsulated
into soft gelatin capsules and evaluated for dissolution in simulated gastric fluid (SGF) at pH 1.2.
Apparatus II method at 50-100 rpm was employed for the dissolution experiments.
Stability study
Capsules of the selected formulations were bottled into HDPE bottles with the use of child resistantclosures and induction sealed for ICH stability studies.

% Drug release

Solubility study:
Preliminary solubility studies for the model drug were conducted in various pharmaceutical excipients(lipid vehicles) to choose appropriate bulk liquid carriers for both approaches. Known amount of drug
was added to vehicle and heated until 45-50˚C to melt the excipients. Vehicle were checked forsolubility based on clarity of the solution and solutions were left to stand 24 hour to check any
precipitation.

3020• From a softgel encapsulation standpoint encapsulation process works with maximum
fill temperature of 42 °C. Above this temperature encapsulation process could facepotential capsule sealing and leaking issues.
• For compritol 888 and other wax based hydrophobic fill approach, encapsulation was
only feasible at a temperature range of 37-42 °C while hydrophilic vehicle based fills
could be encapsulated at room temperature. However, hydrophilic vehicle based fills
became very viscous after 24 hr storage as a result of PEO and Povidone K30 hydration.
• Dissolution in simulated gastric fluid (SGF) showed controlled release of the drug up to12 hour from both approaches. Polyethylene Oxide (PEO) and Povidone K 30 wereused with the hydrophilic vehicles as well as hydrophobic vehicles. Use of hydrophilicvehicles (HLB > 14) which had solubilizing capacity for the drug, resulted in an initial
burst effect as seen from blue line in graph 2. (PEO + Povidone K 30 in hydrophilicvehicle). When the high HLB (hydrophilic-lipophilic balance) vehicle was switched withexcipients in an HLB range of 9-12, the burst effect was mitigated. Faster rate of drug
sedimentation was noted for the hydrophilic Povidone/PEO based systems ascompared to the lipidic systems.
• High variability for drug release was noted for wax/hydrophobic vehicles as comparedto polymer/hydrophilic vehicles. In both instances, a diffusion-based releasemechanism was noted. However due to very low solubility of wax in the dissolution
media only 30-40% of the drug was released from capsule.
• With the use of lipophilic based systems, the burst effect was eliminated which can be
attributed to limited API solubility in the lipophilic vehicles and the use of high melting
lipid (HML) excipients such as Compritol 888 (glyceryl dibehenate), Precirol (glyceryldistearate). However the release from these matrix were variable and incomplete as
shown in graphs.

CONCLUSION(S)1000100

200300400Time (min)Compretol 888 in hydrophobic vehicle

500600700800Geleol in hydrophobic vehicle

1201008060
402000100

200300400500
TIme (min)600• For antitussive agents with a short half-life, the approaches discussed in this work canyield sustained release dosage forms to avoid repeated administrations and increase
patient compliance. Moreover, composition of the formulation can be tuned to make it
feasible for encapsulation while retaining the controlled release efficiency of theformulation.
• The controlled release formulations presented in this research could potentially be
deployed for OTC and prescription molecules across a wide range of therapeutic areas.
In addition, the hydrophilic vehicle-based formulations which displayed the burst
effect could be explored for combination drugs that need immediate and controlled
release delivery.

Drug release from vehicle containing polymeric materials% Drug releaseMETHOD(S)40RESULT(S)

700

800

PEO+Povidone K30 in Hydrophilic vehicle

20% PEO+Povidone K30 in lipid vehicle (HLB - 5)

25% PEO in hydrophilic vehicle

20% PEO+Povidone K30 in hydrophobic vehicle (HLB 1)

Percent drug release (%) vs time (min) graphs for different fill formulat6ions based on hydrophilic and hydrophobicvehicles. The graph on top shows drug release from hydrophobic matrix while graph on bottom shows drug release fromhydrophilic vehicle mixed with polymeric materials. Data shows average of two determinations (n=2).