Solid state behavior of progesterone and its release from Neusilin US2 based liquisolid compacts

Accepted Manuscript Solid state behavior of progesterone and its release from Neusilin US2 based liquisolid compacts N.R. Jadhav, M. Pharm., Ph. D., P.V. Irny, U.S. Patil PII:

S1773-2247(16)30419-1

DOI:

10.1016/j.jddst.2017.01.009

Reference:

JDDST 293

To appear in:

Journal of Drug Delivery Science and Technology

Received Date: 8 September 2016 Revised Date:

27 January 2017

Accepted Date: 29 January 2017

Please cite this article as: N.R. Jadhav, P.V. Irny, U.S. Patil, Solid state behavior of progesterone and its release from Neusilin US2 based liquisolid compacts, Journal of Drug Delivery Science and Technology (2017), doi: 10.1016/j.jddst.2017.01.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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SOLID STATE BEHAVIOR OF PROGESTERONE AND ITS RELEASE FROM

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NEUSILIN US2 BASED LIQUISOLID COMPACTS. Authors

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N. R. Jadhav*, P. V. Irny, U. S. Patil

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Affiliation

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Department of Pharmaceutics

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Bharati Vidyapeeth College of Pharmacy

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Kolhapur-416013, India.

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*

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Prof. N. R. Jadhav, M. Pharm., Ph. D.

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Head of Department

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Department of Pharmaceutics,

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Bharati Vidyapeeth College of Pharmacy

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Kolhapur-416013

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State: Maharashtra (India)

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E-mail: [email protected]

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Phone: +91-231-2637286 Mobile: +919823751579

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Address for Correspondence

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Abstract:

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The aim of present work was to investigate the role of liquisolid technique in improving

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dissolution of high dose Progesterone. Progesterone-PEG 400 dispersions were prepared and

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evaluated for technological properties, and further formulated into liquisolid tablets using

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Neusilin US2 and Syloid 244 FP as a carrier and coat respectively. Due to polymorphic

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behavior of Progesterone, liquisolid tablets were investigated by XRPD, DSC and SEM,

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whereas, improvement in dissolution was studied by in vitro technique. Results of liquid load

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factor and liquid retention potential demonstrated a role of Neusilin US2 and Syloid 244 FP

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as a superior carrier and coat material respectively. Both excipients enabled incorporation of

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higher amount of liquid medication and high Progesterone loading (50 mg). Acceptable

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flowability and compressibility of liquisolids were noted, uncompromising tablettability and

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tablet size. Noteworthy findings of XRPD and DSC suggested polymorphic transition of

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Progesterone from stable α to metastable β form in liquisolid formulation having high liquid

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medication. Consequently, superior dissolution profiles for liquisolid tablets, compared to

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conventional tablet were noted. Hence, it can be concluded that, liquisolid tablets of high

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dose progesterone were successfully formulated using Neusilin US2 and Syloid 244 FP.

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Besides improved dissolution, polymorphic transition was also revealed for Progesterone.

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Keywords: Progesterone, Neusilin US2, Liquisolid compact, Metastable polymorph,

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Dissolution enhancement.

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Chemical compounds studied in this article

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Progesterone (PubChem CID: 5994); Neusilin US2 (PubChem CID: 3084116); Syloid 244

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FP (PubChem CID: 24261); Polysorbate 80 (PubChem CID: 5284448); Propylene glycol

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(PubChem CID: 1030); Polyethylene glycol 400 (PubChem CID: 174); Methanol (PubChem

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CID: 887). 1

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1. Introduction

Progesterone is used in the treatment of secondary amenorrhea, dysfunctional uterine

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bleeding and in combination hormone-replacement therapies [1]. It is administered orally as a

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tablet or capsule in a dose range 100 to 400 mg per day. However, Progesterone exhibits poor

56

aqueous solubility (7µg/ml), and hence, shows poor dissolution rate [2]. Till date, numerous

57

approaches have been adopted towards enhancing solubility and dissolution rate of

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Progesterone. Which includes, addition of Polyethylene glycol 400 (PEG 400) and

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Polysorbate 80 [2], formation of supersaturated solids [3], complexation with Cyclodextrins

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[4,5] formulation into solid dispersion [6], micronization [7,8] etc.

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Additionally, Progesterone being polymorphic, has attracted attention of researchers

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towards it, because, different crystal forms differ in their solubility and hence bioavailability.

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Two polymorphs, stable form I (α-form) and metastable form II (β-form) of Progesterone

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have already been reported [9,10]. Form I and form II has melting point at 128°C and 122°C

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respectively, and form II is more soluble than form I. It has been deliberated that the

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molecules of progesterone in the form I are firmly attached in the lattice due to strong

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hydrogen bonding interactions and hence it is less soluble than form II. Knowing this, and

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considering its poor aqueous solubility, in this investigation polymorphic changes of

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Progesterone in liquisolid formulation and its impact on Progesterone release from liquisolid

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compacts has been studied.

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Besides various techniques reported for solubility and dissolution improvements,

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liquisolid tablet formulation design is a recent and promising [11,12], and stands out amongst

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most, guaranteeing strategies [13]. Liquisolid concept is used to enhance the solubility of

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poorly water soluble drugs at least for the first two hours (active absorption phase) [14].

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Liquisolid systems containing poorly soluble drugs have shown enhanced drug dissolution

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because of its molecular dispersion, increased wetting and large surface area available for 2

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dissolution [15,16]. Such liquisolid system consists of water insoluble drugs dissolved or

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dispersed in a suitable water-miscible nonvolatile solvent system, further converted into a

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dry-looking, non-adherent, free-flowing, and readily compressible powder using carrier and

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coat material [17]. Till date, liquisolid technique has successfully demonstrated improvement

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in in-vitro release of poorly water soluble drugs like Risperidone [14], Famotidine [17],

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Prednisolone [18], Hydrocortisone [19], Methylclothiazide [20], Hydrochlorothiazide [21],

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Nateglinide [22], Carbamazepine [23,24], Nicardipine [25], Naproxen [26] etc. Excipients

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such as Starch, Lactose, Celluloses etc. possessing porous surface with high adsorption

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properties have been used as carriers, and Silica powders like Aerosil, Cab-o-sil etc. have

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been used as coating materials [18] .

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Literature has revealed that, liquisolid technique could be successfully used in low dose

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poorly water soluble drugs, whereas, it limits applicability for the formulation of high dose

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poorly soluble drugs. Higher drug dose requires higher amounts of liquids and to obtain

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liquisolid systems with acceptable flowability and compressibility/compactibility, high levels

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of carriers and coat materials are required. Which, ultimately leads to an unusual increase in

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tablet weight and difficulty in swallowing. Hence, in the present study an attempt has been

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made to incorporate a high dose of Progesterone (up to 50 mg) using Neusilin US2

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(magnesium aluminometasilicate) and Syloid 244 FP (synthetic amorphous silicon dioxide)

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as promising carrier and coat material respectively, whilst maintaining acceptable flowability,

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compactibility and tablet size. PEG 400 and Sodium starch glycolate (SSG) have been used

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as a nonvolatile solvent and super-disintegrant respectively. Eventually, prepared liquisolid

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tablet formulations were evaluated by XRPD, DSC, SEM, FT-IR, flow properties, in-vitro

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dissolution studies etc.

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2. Materials and methods

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2.1

Materials 3

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Progesterone (Unicure remedies, Vadodara, Gujrat, India). Neusilin US2 (Gangwal

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Chemicals, Mumbai, Maharashtra, India), Syloid 244 FP (Grace Davidson, Mumbai,

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Maharashtra, India), Polyethylene glycol 400 (Sigma–Aldrich, Poole, UK), Sodium starch

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glycolate (Pure Chem Laboratories, Pune, Maharashtra, India) were kind gift to us. All other

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chemicals and solvents were of analytical grade.

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2.2

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Solubility studies

Solubility of Progesterone was screened in three different nonvolatile solvents, i.e. PEG

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400, Polysorbate 80 and Propylene glycol. Saturated solutions of Progesterone were prepared

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by adding an excess to aforesaid vehicles (10 ml) and shaking in the orbital shaker (Remi

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Instruments Ltd, Mumbai, India) for 48 hr. at 250C. Then, the supernatant was filtered

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through 0.45 µm milli pore filter, appropriately diluted with Methanol and analyzed by UV-

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visible spectrophotometer (Shimadzu, Japan) at λmax 240 nm against blank (specific solvent

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without drug). Three determinations were carried out for each sample separately to calculate

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the solubility of Progesterone

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2.3

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Determination of the optimal flowable liquid retention potential (φ–value) for Neusilin US2 and Syloid 244 FP

Angle of slide method has been widely reported in the literature to determine the flowability

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of powder excipients used for liquisolid systems [27]. For successful fabrication of free

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flowing liquisolid system, mathematical models have been suggested to calculate optimum

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quantities of carrier and coat material required to incorporate sufficient amount of liquid

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medication [28]. The model equations are based on flowable (φ – value) and compressible

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(ψ–number) liquid retention potential of carrier and coat material. The φ–value of a powder is

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defined as the maximum amount of a given non-volatile liquid that can be retained inside its

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bulk per unit weight of powder whilst maintaining acceptable flowability [23]. This φ – value

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is determined by estimating flow of powder/liquid admixture in terms of angle of slide and

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this value is taken at an angle of slide corresponding to 33° (for optimal flow properties). The

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φ–value is calculated by using following equation,

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φ =







(1)



The ψ value of powder is the maximum amount of liquid, the powder can retain inside its

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bulk per unit weight of powder whilst maintaining acceptable compactibility, to produce

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compacts having satisfactory hardness and friability, with no liquid squeezing out during

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compression. The ψ-number of powders can be determined using pacticity theory [23].

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An acceptably flowing and the compressible liquisolid system can be prepared only if a

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maximum liquid load on the carrier material does not exceed. This amount of liquid is termed

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as a liquid load factor (Lf) and is defined as the weight ratio of the liquid medication (W) and

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carrier powder (Q) in the system, given as under,

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(2)

For powder substrates consisting certain amount of carrier and coat material, there should be

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specific Lf in order to produce acceptably flowing liquisolid systems. Such Lf depends upon

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φ - value of both carrier and coat and also depends upon excipients ratio (R). The R is a ratio

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of the weights of the carrier (Q) and coat (q) material present in the formulation. =

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(3)

The R and Lf of the formulations are related as follows,

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Lf = φ CA + φ CO (1/R)

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Lf value can be calculated from the linear relationship of Lf versus 1/R considering the values

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of φ CA and φ CO obtained from flow studies mentioned above.

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(4)

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In current study, the flowable liquid retention potential of powder excipients (Neusilin

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US2 and Syloid 244 FP) admixed with the liquid vehicle was evaluated by measurement of

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angle of slide. Several homogeneous liquid vehicle/powder admixtures containing 10 g of the 5

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carrier/coat material with increasing amount of the liquid vehicle (PEG 400) were prepared

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and placed on the polished metal plate. Subsequently, the plate was tilted gradually until the

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liquid/ powder admixture just slides. The angle formed between plate and horizontal surface

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was defined as the angle of the slide (θ). The φ-value of each liquid/powder admixture was

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then calculated by using the Eq. (1).

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Further, φ–values were plotted against the corresponding angles of slide θ (Fig. 1). The

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angle of slide θ for optimal flow properties corresponding to 330 represents the flowable

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liquid-retention potential (φ-value) of the powder [27].

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2.4

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Progesterone liquisolid formulations, designated as LS-1 to LS-5 (Table 1) were prepared

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using PEG 400 as a nonvolatile vehicle containing Progesterone in concentrations ranging

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from 10 to 30% w/w. The required quantity of Progesterone was dispersed in the liquid

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vehicle (PEG 400) and heated to 400C with constant stirring until a homogenous dispersion,

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called as liquid medication was obtained. All liquisolid formulations contained Neusilin US2,

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as carrier and Syloid 244 FP as coating material in fixed powder ratio (R) of 10. The value of

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R as 10 was corroborated by preparing several formulations with varying the excipient ratio

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from 5 to 20. The appropriate amounts of carrier and coat materials were derived from their φ

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-value (Fig. 1) and liquid load factors (Lf), as in Eq. (2) - (4). Lf was calculated by

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substituting the flowable liquid retention potential of carrier (φ

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liquid retention potential of coat (φ CO-value) into Eq. (4). By knowing liquid load factors

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(Lf) and amount of liquid medication (W) corresponding to 50 mg Progesterone, appropriate

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amounts of carrier (Q) and coat (q) (Table 1) were calculated by using Eqs. (2), (3).

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Subsequently, hot liquid medication equivalent to 50 mg Progesterone was incorporated into

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calculated quantity of Neusilin US2 and Syloid 244 FP. The mixing process was carried out

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using a three step standard procedure previously described by Spireas and Bolton [28] and

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CA-value)

and the flowable

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Preparation of liquisolid powders

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Spireas [29]. In the first step, mixing was carried out at a rate of one rotation per second for

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approximately one minute in order to uniformly mix the liquid medication with carrier and

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coat. In the second, the liquid/powder admixture was evenly spread as a uniform layer on the

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surface of a mortar and left standing for approximately 5 min to allow the drug solution to be

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absorbed inside powder particles. In the third, the powder was scraped off from the mortar

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surface using an aluminum spatula. Finally, the system was blended with 8% SSG as a super

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disintegrant. Schematic representation of mechanism of conversion of liquid medication to

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liquisolid system is given in Fig. 2.

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2.5

Flow properties of liquisolid powders

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The flow properties of the liquisolid systems were evaluated by determination of the

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angle of repose, Carr’s index and Hausner’s ratio [30–33]. Angle of repose was determined

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by fixed funnel free standing cone method [30,31]. The procedure was performed in triplicate

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and the average angle of repose was calculated for each liquisolid system. For bulk density

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measurements, bulk density apparatus (Lab Hosp Corporation, Mumbai, India) was used. The

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prepared liquisolid powders were weighed and poured into a 100 ml cylinder. The poured

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bulk volume (BV) and the tapped volume (TV) were recorded which in turn was used to

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calculate the poured bulk density (BD) and the tapped density (TD) in g/ml. Carr’s

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compressibility index (CCI) and Hausner’s ratio (HR) was calculated to investigate the

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flowability of the powders using the following Eq. (5) and (6),

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=

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2.6

(

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(5) (6)

Pressure- relative density and tensile strength studies

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The liquisolid powder formulations (LS-1 to LS-5) were compressed using a hydraulic

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press (Techno search Ins., Mumbai, India) with 13-mm flat-faced punch and die at pressures

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ranging from 1 to 7 tons for 1 min. dwell time. Prior to compression, die and punches were 7

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lubricated with 2% w/v dispersion of Magnesium stearate in Acetone. Each time, compacts

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were prepared in triplicate and allowed to recover elastically over Silica gel for 24 hours prior

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to evaluation. Subsequently, the dimensions (diameter and thickness) and weight of compacts

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were determined. The relative density (ρr) was calculated as the ratio of apparent density (ρA)

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of the compact to the true density of compact (ρT) as shown in Eq. (7)

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ρ# = ρ$

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ρ

%

(7)

Data obtained were subject to Heckel equation for investigation of pressure relative

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density relationship using Eq. (8) [34].

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ln (

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) *+

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, = -. / + 1

(8)

Where P is applied pressure, Ky (slope of the linear portion of the plot) is reciprocal of the

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mean yield pressure (MyP) of the material and A is the intercept. The MyP is inversely

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related to the ability of the material to undergo plastic deformation under pressure and A is a

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function of initial compact volume.

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The same compacts used in Heckel analysis were used for tensile strength (σt)

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determination. All batches LS-1 to LS-5, after determination of the diameter (D) and height

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(h), were subject to determination of crushing force (F) by hardness tester (Lab Hosp,

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Mumbai, India) and tensile strength (σt) calculated using Eq. (9).

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2 = 6.

3∙5

(9)

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For compactibility assessment, Leuenberger analysis was carried out by fitting the data

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of Heckel analysis and tensile strength to Eq. (10) [35]. A nonlinear plot of tensile strength

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(σt) versus the product of compaction pressure (P) and relative density (ρr) was obtained.

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2 = 2 89: (1 − <

*+×=×> )

(10)

Where σtmax is maximum tensile strength (compactibility) when P will be infinite and relative density ρr will be equal to 1 (zero porosity) and γ is compression susceptibility. 8

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2.7

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Scanning electron microscopy (SEM)

SEM coupled EDAX Model-JEOI-SEM 6360 was utilized to assess the topological

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characteristics of the raw materials and the drug-carrier systems. The samples were coated

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with platinum using auto fine coater for 75 sec at a 40 mA operating current and thickness

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was maintained below 25 nm.

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2.8

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Fourier transform infrared spectra of Progesterone, Neusilin US2, Syloid 244 FP, liquisolid

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formulations and the physical mixture were recorded. About 5 mg of sample was mixed

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thoroughly with 100 mg potassium bromide powder and compacted under vacuum at a

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pressure of about 12,000 psi for 3 min. The resulting disk was mounted in a suitable holder in

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FT-IR spectrophotometer (Jasco FTIR- 4100, Japan) and IR spectrum was recorded in the

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frequency range of 4000-550 cm-1 at 4 cm-1 resolution.

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2.9

X-ray diffraction (XRD)

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XRD patterns were recorded for Progesterone, physical mixture and formulations LS-1

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and LS-5, using Philips PW 3710 X-ray diffractometer. The samples were exposed to Cu-Kα

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radiation (45 kV, 40 mA) at a scan rate of 2o/min over the 2θ range of 3–60o. The results were

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obtained as peak height (intensity) versus 2θ.

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2.10 Differential scanning calorimetry (DSC)

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The thermograms of the Progesterone, Neusilin US2, Syloid 244 FP, physical mixture

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and samples of LS-1 and LS-5 were recorded using DSC (DSC-60 Shimadzu, Japan).

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Approximately 3-4 mg samples were weighed and sealed in aluminum pans. The thermal

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behavior of samples was investigated at a scanning rate of 10°C/min in the temperature range

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of 0°C to 180°C.

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2.11 Preparation of liquisolid compacts

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The prepared liquisolid powders (LS-1 to LS-5) were compressed into compacts using a

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13-mm flat-faced punch and die set on hydraulic press. Even, conventional compact of

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Progesterone (DCT) was also prepared containing 50 mg Progesterone, 400 mg Neusilin

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US2, 40 mg Syloid 244 FP and 8% of SSG as super disintegrant. The excipients were

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weighed and mixed in mortar for 15 min and subject to compaction. To evaluate the effect of

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excipient ratio on dissolution profile, several formulations were prepared with varying the

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carrier to coat ratio from 5 to 20 and their dissolution profiles were compared.

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2.12 Characterization of compacts

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2.12.1 Weight variation, drug content uniformity, tablet hardness, friability, and

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disintegration time

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A weight variation study was carried out by randomly selecting twenty tablets from each

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tablet formulation (LS-1 to LS-5) and weighed individually. The average weight of all tablets

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and percentage deviation from the mean for each tablet was determined. For drug content uniformity studies, ten tablets from each batch were chosen randomly,

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each tablet was weighed and crushed individually. Crushed tablet powders were dissolved in

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Methanol. The solution was filtered using 0.45 µm Whatman filter paper and drug content

265

was measured using UV/Visible spectrophotometer (Shimadzu, Japan) at λmax 240 nm. The

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percentage of drug content in each tablet was calculated against the average drug content,

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according to compendial specifications [36].

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Tablet hardness was determined in triplicate for each formulation by measuring the force in Kg/cm2 required to crush the tablet using hardness tester (Lab Hosp, Mumbai).

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The friability of the tablets was determined using a friability tester (Roche friabilator).

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The drum was rotated for 4 min at 25 RPM. The weight loss from 10 tablets was determined,

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and percentage of friability was calculated.

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The disintegration test was performed at 37 ± 1 C in distilled water for six tablets from

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each formulation using tablet disintegration test apparatus. The tablets were considered

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completely disintegrated when there was no residue remaining on the screen or a residue

276

consisted of a soft mass with no palpably firm or un-moistened core [36].

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2.12.2 In vitro dissolution studies

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In vitro dissolution studies were performed for LS-1 to LS-5 and DCT using USP

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dissolution test apparatus II (Electrolab TDT-08L) in water containing 2% SLS as a

280

dissolution medium. The volume of dissolution medium was 900 ml maintained at a

281

temperature of 37 ± 1°C at a stirring speed of 100 RPM. Five milliliters of samples were

282

collected at time intervals of 5, 10, 15, 30, and 60 min. The withdrawn samples were replaced

283

by an equal amount of the fresh dissolution medium to maintain a constant volume. The

284

samples withdrawn at different time intervals were analyzed spectrophotometrically at 240

285

nm for determination of the Progesterone content. The in vitro release profiles of liquisolid

286

tablets and conventional tablets were compared using similarity factor, f2, as defined by

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following Eq. (11)

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?3 = 50 log C(1 + D ∑D )(

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− F )3 ,

G.H

× 100 I

(11)

Where n is the number of time points at which % drug dissolved is determined, Rt % drug

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dissolved of one formulation at given time point and Tt % drug dissolved of the formulation

291

to be compared at the same time point.

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2.13 Stability studies

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The tablet formulations LS-1, were stored at 40 C ± 2 C temperature and 75% ± 5%

294

relative humidity conditions for three months. The stored tablets were evaluated for hardness

295

and drug dissolution. The dissolution data of aged tablets were compared with un-aged

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tablets.

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2.14 Statistical analysis

The dissolution profile of LS1 and DCT was evaluated statistically using one-way

299

analysis of variance (ANOVA). Differences between two related parameters were considered

300

statistically significant for P<0.05. The statistical analysis was performed using statistical

301

software package SYSTAT (Ver. 12.00.08).

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3. Results and Discussion

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3.1

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Solubility of Progesterone in various non-volatile liquid vehicles

Concentration estimates of pure Progesterone in methanol showed good linearity (r =

305

0.998) over the concentration range 2-12 µg/ml obeying Beer- Lambert’s law. The values of

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slope and intercept of calibration curve were 0.065 & 0.020 respectively.

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The solubility of Progesterone in Distilled water, Tween 80, Propylene glycol, and PEG

308

400 was found to be 0.0007±0.00014, 1.11±0.33, 1.44±0.56, 8.92±0.03 % w/w respectively.

309

Progesterone exhibited highest solubility in PEG 400 which is one of the most widely used

310

co-solvents for improving the aqueous solubility of hydrophobic drugs; hence it was selected

311

to prepare the liquid medication [2]. In liquisolid formulations, higher solubility means, more

312

amount of drug gets dissolved in the liquid vehicle prior to the adsorption onto the carrier.

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Determination of φ -value and Lf

The relationship between angle of slide and corresponding φCA - value and φCO - value of

315

Neusilin US2 and Syloid 244FP respectively is depicted in Fig. 1. The φCA value for Neusilin

316

US2 and φCO value for Syloid 244 FP were found to be 0.88 and 3.7 respectively, which were

317

highest φ -values, compared to commonly used carrier and coat materials reported in

318

literatures[37]. With carrier to coat ratio (R) of 10, the Lf value was found to be 1.25 for

319

Neusilin US2 and Syloid 244FP as calculated by Eq. (4). Indeed, Eq. (2) demonstrated that Lf

320

value is inversely proportional to the amount of carrier required in the formulation.

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Accordingly, higher the value of Lf less is the amount of carrier and coat material required to

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produce dry-looking, non-adherent, free flowing and readily compactible liquisolid

323

formulations. From the literature, Lf value reported for Avicel PH-102 and Aerosil 200

324

combination was 0.331 [25] and that for Avicel PH-200 and Aerosil 200 combination was

325

0.26 [38]. Similar work has demonstrated that if Lf is high, the use of additional additives

326

such as PVP is not required, thus reduces the tablet weight significantly [24]. It has been

327

observed that liquisolid formulations with lower drug concentration (LS-1), as revealed in

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table 1, require more liquid vehicles as well as the carrier and coat materials, and

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consequently larger tablets were produced compared to those containing higher drug

330

concentrations.

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Generally Carr’s index below 15% indicates good flow whereas above 25% indicates

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poor flowability [39]. Hausner’s ratio below 1.25 is an indicator of good flowability whereas

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above it indicates poor flowability. The results of powder flowability of liquisolid

335

formulations have been given in Table 2. Formulations LS-1 to LS-3 demonstrated good flow

336

properties whilst LS-4 and LS-5 had passable flow properties [36]. Syloid 244 FP, which was

337

used as a coat to absorb the excessive liquid, also acted as a glidant (concentration of 0.1-

338

0.5%). Thus, it improved the powder flowability in LS-1 to LS-3 formulations. In case of LS-

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4 and LS-5 formulations, because of high concentration of the drug dispersed in the liquid

340

vehicle, less carrier and coat material was required compared to the other formulations to

341

convert the dispersion into a free flowing powder. As a result of less amount of Syloid 244

342

FP in the LS-4 and LS-5 formulations, they exhibited passable flow properties. Also, liquid in

343

these formulations might not have completely adsorbed leading to formation of agglomerates

344

hampering flowability.

345

3.4

AC C

EP

TE D

332

Heckel analysis, Tensile strength, and Leuenberger analysis

13

ACCEPTED MANUSCRIPT

Heckel analysis revealed mean yield pressure (tons) for LS -1 to LS -5 formulations to be

347

1.63 ± 0.170; 1.32 ± 0.341; 1.22 ± 0.364; 1.33 ± 0.078; 0.97 ± 0.198 respectively. All

348

formulations were found to undergo plastic deformation because, plastic powders are

349

characterized by smaller values for MyP. Analysis of aforesaid values evince poor

350

compressibility of LS-1 formulation, which could be attributed to more amount of carrier and

351

coat material with poor compressibility.

RI PT

346

The strength and extent of interparticulate interactions amongst solid particulates decide

353

the tensile strength of compacts. The tensile strength of compacts was found to decrease from

354

LS-1 to LS-5; 30.92 ±0.12; 25.79 ±0.23; 14.57 ±0.26; 7.56 ± 0.30; 5.29 ± 0.42 Kg/cm2

355

respectively. From aforesaid data, it is evident that, LS-1 formulation demonstrated poor

356

compressibility, nonetheless excellent tensile strength.

M AN U

SC

352

The results of Heckel analysis and tensile strength were further supported by findings of

358

Leuenberger analysis. Maximum tensile strength (σtmax), a measure of compactibility, were

359

found to be 30.76, 24.70, and 14.80 for LS-1 to LS-3 respectively. Analysis of these values

360

confirmed that all formulations undergo plastic deformation. Further, Heckel analysis and

361

Leuenberger

362

compactibility of LS-1 formulation.

363

3.5

also

mutually

corroborated

acceptable

compressibility

and

EP

SEM

analysis

TE D

357

Crystalline nature of Progesterone and non-crystalline form of liquisolid systems (LS-1

365

and LS-5), is clearly evident from SEM microphotographs shown in Fig. 3. Thus, liquisolid

366

formulation consists of a major fraction of the drug in molecularly dispersed state and the

367

remainder in amorphous state, contributing towards the enhanced drug dissolution.

368

3.6

AC C

364

Fourier transform infrared (FT-IR)

369

The characteristic absorption bands of carbonyl stretching between 1660 and 1690 cm-1

370

are noted in FT-IR spectra of Progesterone, liquisolid (LS-1 and LS-5) and DCT. None of 14

ACCEPTED MANUSCRIPT

371

unfavorable interaction was reported between the drug and the excipients, since all the major

372

peaks were retained in the FTIR spectra of the formulations shown in Fig 4.

373

3.7

X-Ray Diffraction studies Progesterone exists in two interconvertible crystal forms of equal physiological activity,

375

as a stable form I (α-form) and metastable form II (β-form) [9]. In diffractogram, the

376

characteristic X-ray diffraction peaks of Progesterone appears at 2θ value 16.9o for α-form,

377

and 16.1° for β-form. [40,41]. Fig 5 depicts sharp, distinct peaks notably at 2θ diffraction

378

angles 12.8°, 14.6°, 15.4° and 16.9° indicating stable crystalline α-form of pure Progesterone.

379

And, formulation LS-1 showed a distinct diffraction peak at 16.1°, whilst, LS-5 showed a

380

peak at 16.9°. Appearance of distinct diffraction peak at 16.1° in diffractogram of the LS-1

381

system has indicated conversion of α-form to the more soluble β-form. However, in LS-5

382

formulation peak reappeared at 16.9° indicated re-crystallization of Progesterone to the less

383

soluble α-form. As anticipated characteristic peaks of Progesterone were observed in the

384

physical mixture demonstrating its crystalline structure. The loss of crystallinity in liquisolid

385

formulations was attributed to solubilization of drug in a liquid vehicle, and subsequent

386

adsorption on carrier and coat [23].

387

3.8

TE D

M AN U

SC

RI PT

374

EP

Differential Scanning calorimetry

Thermal behavior of the Progesterone, excipients and liquisolid formulations have been

389

shown in Fig. 6. Sharp characteristic endothermic peak at 128.35°C corresponding to melting

390

temperature (Tm) of pure Progesterone was observed and was in agreement with melting

391

point of α-form reported at 128°C, which is considered to be the thermodynamically stable

392

polymorph [9,10]. Interestingly, DSC thermograms of LS-1 formulation showed reduction in

393

depth of endothermic peak and shift to 122.2°C, indicating molecular dispersion of

394

Progesterone in liquisolid formulation, and recrystallization of Progesterone to metastable but

395

more soluble β-form respectively. The reason for recrystallization of Progesterone could be

AC C

388

15

ACCEPTED MANUSCRIPT

deciphered on the ground of achieving complete solubilization of Progesterone in PEG 400

397

due to heating at 40°C, aimed to achieve a high degree of supersaturation, which on the

398

liberation of supersaturation at ambient temperature, causes crystallization. During the

399

processing of this supersaturated solution into the liquisolid formulation in the presence of

400

Neusilin US2, some of the molecularly dispersed drug might have also been recrystallized to

401

β-form. This polymorphic transformation of drug, preferably into β-form might be

402

thermodynamically favored due to its possible interactions with Neusilin US2. However,

403

such transformation has not taken place in LS-5 formulation, with high drug concentration in

404

liquid medication, due to liberation of supersaturation on existing Progesterone crystals

405

acting as a nuclei, thus favoring α-form. Thermogram of Neusilin US2 and Syloid 244FP

406

displayed broad endothermic peaks [42].

407

3.9

408

3.9.1

M AN U

SC

RI PT

396

Evaluation of liquisolid and DCT formulations

Uniformity of tablet weight, drug content uniformity, tablet hardness, friability and disintegration test.

TE D

409

All liquisolid and conventional tablets complied with the weight uniformity test

411

mentioned in British Pharmacopoeia [36]. Also, all liquisolid and conventional tablets met

412

compendial content uniformity criteria, in which individual content was between 85% and

413

115% of the average content. The liquisolid and conventional tablets complied with friability

414

test as friability was less than 1% and did not crack, split or break. The results of hardness,

415

weight variation, friability test and disintegration test have been given in Table 3. Therefore,

416

it can be affirmed that all formulations can withstand fracturing and attrition during normal

417

handling, packaging and transporting processes.

418

3.9.2

AC C

EP

410

In vitro dissolution studies

419

In-vitro dissolution profile of liquisolid and conventional tablets of Progesterone in water

420

with 2% SLS as dissolution media has been depicted in Fig. 7. Comparatively enhanced 16

ACCEPTED MANUSCRIPT

dissolution of Progesterone was evident from liquisolid tablets, compared to DCT. The

422

percentage of Progesterone dissolved from LS-1, LS-2, LS-3, LS-4 and LS-5 at 60 min was

423

92.3±0.4%, 84.2±0.2%, 71.6±0.4%, 72.3±0.1% and 67.9±0.4% respectively, whilst

424

dissolution from DCT was hardly 44.1±0.4%. The higher dissolution rates observed for

425

liquisolid formulations could be attributed to the significantly larger surface area of the

426

molecularly dispersed drug particles. Even, the wetting properties of drug particles might

427

have contributed due to its dispersion in liquid vehicle PEG 400, imparting hydrophilicity

428

[43]. Also PEG 400 might have increased the saturation solubility of the drug in the diffusion

429

layer with resultant increase in concentration gradient and hence the dissolution rate [43].

SC

RI PT

421

Liquisolid formulations with smaller drug concentration (LS1 to LS-3) had similar

431

dissolution rates, but were higher in comparison to the dissolution rates exhibited by

432

liquisolid formulations containing a higher drug concentration (LS-4 and LS-5). Such

433

difference in dissolution rate could be attributed to the difference in extent of drug present in

434

the molecularly dispersed form and undissolved drug. In LS-1, liquid medication had 89%

435

w/w of the drug in solubilized state, whilst, in LS-5 only 29% w/w of Progesterone was in

436

solubilized state. The amount of drug present in the molecularly dispersed form in the liquid

437

medication was calculated by the Eq. (12) [19].

438

J8 = K L

K

M

EP

TE D

M AN U

430

(12)

Where, Fm is the fraction of molecularly dispersed or dissolved drug in liquid medication

440

of the prepared liquisolid formulation, Cs is the saturation solubility of Progesterone in the

441

liquid vehicle and Cd is the drug concentration in the liquid medication. Calculated values of

442

Fm for LS-1 to LS-5 formulations are given Table 1. According to Spireas et al. Fm value

443

cannot exceed unity [19]. Since each liquisolid system contains the same amount of drug, the

444

amount of liquid varied results in different concentration of drug in liquid medication (Cd).

445

The saturation solubility of Progesterone in PEG 400 is 8.92% w/w hence after applying Eq.

AC C

439

17

ACCEPTED MANUSCRIPT

(12), Fm value for LS-1 was found to be 0.89. Thus, it can be concluded that 89% w/w of the

447

drug was in a solubilized state in LS-1, whilst only 29% w/w of Progesterone was in a

448

solubilized state in LS-5. Further, the DSC and XRD studies have shown that there was some

449

recrystallization of Progesterone in liquisolid formulations. Hence, Progesterone could

450

precipitate in silica pores (Syloid 244 FP) especially in formulations with high drug

451

concentration, showing corresponding decrease in dissolution rate. The potential of

452

Progesterone to precipitate within the silica pores depend on the solubility of the drug in the

453

solvent, the degree of saturation of the drug solution, and the interactions with excipients.

454

From DSC and XRD studies, it was noted that progesterone recrystallized to metastable β-

455

form in liquisolid formulation with low drug concentration in liquid medication, whilst it

456

recrystallized to less soluble α-form in liquisolid formulation with high drug concentration in

457

liquid medication. Which could explain the higher dissolution rate with LS-1 than LS-5 even

458

after some drug precipitation.

M AN U

SC

RI PT

446

The effect of various ratios of Neusilin US2 to Syloid 244 FP on the dissolution profile of

460

liquisolid compacts is shown in Fig. 8. Interestingly, when the ratio of Neusilin US2 to Syloid

461

244 FP was reduced from 20:1 to 15:1 and further to 10:1, the dissolution rate of

462

Progesterone increased gradually but showed a slight decrease when the ratio was further

463

reduced to 5:1. This could be attributed to increase in liquid medication with a decrease in R

464

value. However, with further decrease in R to 5, a decrease in dissolution rate was noted due

465

to excessive building of coat on the core.

466

3.10 Stability Studies

AC C

EP

TE D

459

467

The results of stability studies have shown that the hardness and dissolution of tablets

468

were not affected significantly after aging of tablet at 40 °C ± 2 °C and 75% ± 5% relative

469

humidity. There was no significant difference between the hardness of fresh (6.8 Kg/cm2) and

470

aged (7.0 Kg/cm2) liquisolid tablets. Fig. 9 shows similar dissolution profiles of fresh and 18

ACCEPTED MANUSCRIPT

471

aged liquisolid tablets with a similarity factor of 70. This showed that aging had no

472

significant effect on the drug release profile of the Progesterone liquisolid tablets.

473

4. Conclusion Neusilin US2 and Syloid 244 FP have been proved to be a better carrier and coat material

475

for liquisolid tablets. Rapid dissolution rates for liquisolid formulations of Progesterone

476

compared to conventional tablets were attributed to increased wettability, presence of

477

molecularly dispersed drug, conversion of Progesterone to amorphous form and polymorphic

478

transformation to more soluble metastable β-form as confirmed from thermal and

479

diffractometric studies. Agreeably, Neusilin US2 has been found to be a better carrier for

480

adsorption of molecularly dispersed drug in liquisolid formulations. First time, liquisolid

481

technique has been successfully optimized for incorporation of ever reported high dose of

482

drug.

483

Acknowledgements

484

The authors wish to thank Gangwal Chemicals, Mumbai for providing gift sample of Neusilin

485

US2 and Head, University Instrumentation Scientific Centre (UISC), Shivaji University,

486

Kolhapur for DSC and powder X ray diffraction studies.

487

Funding:

488

This research did not receive any specific grant from funding agencies in the public,

489

commercial, or not-for-profit sectors.

490

Declaration of Interest:

491

The authors report no declarations of interest.

492

References:

493

[1] T. Levy, Y. Yairi, I. Bar-Hava, J. Shalev, R. Orvieto, Z. Ben-Rafael, Pharmacokinetics

494

of the progesterone-containing vaginal tablet and its use in assisted reproduction,

495

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AC C

EP

TE D

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474

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cyclodextrin to enhance solubility of progesterone., AAPS PharmSciTech. 4 (2003) 1–5. [3] A. Funke, T. Wagner, R. Lipp, Stabilised supersaturated solids of lipophilic drugs, US8715735 B2, 2014. https://www.google.com/patents/US8715735. [4] K. Uekama, F. Hirayama, T. Irie, Cyclodextrin Drug Carrier Systems, Chem Rev. 98

RI PT

497

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SC

496

[6] S. Manchanda, M.S. Rathore, Solubility enhancement of Progesterone by solid

505

dispersion approach, in: AAPS Annu. Meet. Expo., AAPS Annual meeting and

506

Exposition, Los Angeles CA, USA, 2009.

507 508

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[7] W.S. Maxson, J.T. Hargrove, Bioavailability of oral micronized progesterone., Fertil. Steril. 44 (1985) 622–626.

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oral administration of micronized progesterone., J. Steroid Biochem. 26 (1987) 241–249.

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[9] F. Wang, J.A. Wachter, F.J. Antosz, K.A. Berglund, An Investigation of Solvent-

512

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513

Spectroscopy, Org. Process Res. Dev. 4 (2000) 391–395.

EP

TE D

509

[10] R. Tripathi, S. V Biradar, B. Mishra, A.R. Paradkar, Study of Polymorphs of

515

Progesterone by Novel Melt Sonocrystallization Technique: A Technical Note, AAPS

516

PharmSciTech. 11 (2010) 1493–1498.

AC C

514

517

[11] Y. Javadzadeh, M.R. Siahi, S. Asnaashari, A. Nokhodchi, Liquisolid technique as a tool

518

for enhancement of poorly water-soluble drugs and evaluation of their physicochemical

519

properties., Acta Pharm. 57 (2007) 99–109.

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[12] B. Vranikova, J. Gajdziok, Liquisolid systems and aspects influencing their research and 20

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[13] S.B. Aher, D.M. Shinkar, R.B. Saudagar, Liquisolid Dosage System : A Novel Approach for Dosage formulation, Int. J. Pharma Sci. Res. 6 (2015) 74–79. [14] S. Kaparthi, P.R.S. Babu, Risperidone liquisolid compacts–Formulation and evaluation, Der Pharm. Sin. 6 (2015) 9–15.

RI PT

521

[15] B. Vraníková, J. Gajdziok, D. Vetchý, Modern Evaluation of Liquisolid Systems with

527

Varying Amounts of Liquid Phase Prepared Using Two Different Methods, Biomed Res.

528

Int. 2015 (2015) 1–12.

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[16] M. Kharwade, M. Sneha, Review on Pioneering Technique - Liquisolid Compact and Applications ., Res. J. Pharm. Biol. Chem. Sci. 6 (2015) 220–227.

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[17] R.H. Fahmy, M.A. Kassem, Enhancement of famotidine dissolution rate through

532

liquisolid tablets formulation: in vitro and in vivo evaluation., Eur. J. Pharm. Biopharm.

533

69 (2008) 993–1003.

537 538 539 540 541 542 543

TE D

536

compacts, Int. J. Pharm. 166 (1998) 177–188. [19] S. Spireas, S. Sadu, R. Grover, In vitro release evaluation of hydrocortisone liquisolid tablets., J. Pharm. Sci. 87 (1998) 867–872.

EP

535

[18] S. Spireas, S. Sadu, Enhancement of prednisolone dissolution properties using liquisolid

[20] S. Spireas, T. Wang, R. Grover, Effect of Powder Substrate on the Dissolution Properties of Methyclothiazide Liquisolid Compacts, Drug Dev. Ind. Pharm. 25 (1999) 163–168.

AC C

534

[21] K.A. Khaled, Formulation and evaluation of hydrochlorothiazide liquisolid tablets, Saudi Pharm. J. 6 (1988) 39–46. [22] I.A. Syed, G. Bhavani, Liquisolid technique based tablets for enhancement of dissolution, Indo Am. J. Pharm. Res. 4 (2014) 2392–2400.

544

[23] S.A. Tayel, I.I. Soliman, D. Louis, Improvement of dissolution properties of

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Carbamazepine through application of the liquisolid tablet technique, Eur. J. Pharm. 21

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Biopharm. 69 (2008) 342–347.

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[24] Y. Javadzadeh, B. Jafari-Navimipour, A. Nokhodchi, Liquisolid technique for

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dissolution rate enhancement of a high dose water-insoluble drug (carbamazepine), Int.

549

J. Pharm. 341 (2007) 26–34.

554 555 556 557 558 559

RI PT

553

[26] N. Tiong, A.A. Elkordy, Effects of liquisolid formulations on dissolution of naproxen, Eur. J. Pharm. Biopharm. 73 (2009) 373–384.

SC

552

floating tablets of nicardipine, Int. J. Trends Pharm. Life Sci. 1 (2015) 45–57.

[27] S.S. Spireas, C.I. Jarowski, B.D. Rohera, Powdered Solution Technology: Principles and Mechanism, Pharm. Res. 9 (1992) 1351–1358.

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[25] P. Ramya, S.S. Latha, Preparation & comparative evaluation of liquid compacts &

[28] S. Spireas, S.M. Bolton, Liquisolid systems and methods of preparing same, US5800834 A, 1998. http://www.google.com/patents/US5800834.

[29] S. Spireas, Liquisolid systems and methods of preparing same, US6423339 B1, 2002. http://www.google.com/patents/US6423339.

TE D

550

[30] P.E. Luner, L.E. Kirsch, S. Majuru, E. Oh, A.B. Joshi, D.E. Wurster, M.P. Redmon,

561

Preformulation Studies on the S-Isomer of Oxybutynin Hydrochloride, an Improved

562

Chemical Entity (ICETM), Drug Dev. Ind. Pharm. 27 (2001) 321–329.

564

[31] J. Staniforth, Powder flow, in: M. Aulton (Ed.), Pharm. Sci. Dos. Form Des., Second Ed., Churchill Livingstone, Longman group: Edinburgh, 2002: pp. 197–210.

AC C

563

EP

560

565

[32] M. V Velasco, A. Muñoz-Ruiz, M.C. Monedero, M.R. Jiménez-Castellanos, Flow

566

Studies on Maltodextrins as Directly Compressible Vehicles, Drug Dev. Ind. Pharm. 21

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(1995) 1235–1243.

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[33] G.E. Amidon, Physical and mechanical property characterization of powders, in: H.G.

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Brittain (Ed.), Phys. Charact. Pharm. Solids, Drugs Pharm. Sci., Marcel Dekker Inc.,

570

New York, 1995: pp. 282–317. 22

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571

[34] S.P. Singh, C.N. Patra, S.C. Dinda, A Systematic Study on Processing Problems and In-

572

vitro Release of Saraca indica Caesalpiniaceae Bark Powder Tablets, Trop. J. Pharm.

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Res. 11 (2012) 387–395. [35] S. Satya Prakash, C.N. Patra, C. Santanu, P. Hemant Kumar, V.J. Patro, M.V. Devi,

575

Studies on Flowability, Compressibility and In-vitro Release of Terminalia Chebula

576

Fruit Powder Tablets., Iran. J. Pharm. Res. IJPR. 10 (2011) 393–401.

RI PT

574

[36] British Pharmacopoeia, vol. IV, 2008.

578

[37] B. Vraníková, J. Gajdziok, Evaluation of sorptive properties of various carriers and

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coating materials for liquisolid systems, Acta Pol. Pharm. - Drug Res. 72 (2015) 539–

580

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[38] C.P. Kumar, P. Venugopalaiah, C.P. Kumar, K. Gnanaprakash, M. Gobinath, Liquisolid

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systems - an emerging strategy for solubilization & dissolution rate enhancement of BCS

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class-II drugs, Int. J. Pharm. Rev. Res. 3 (2013) 56–66.

[39] A.A. Elkordy, X.N. Tan, E.A. Essa, Spironolactone release from liquisolid formulations

585

prepared with CapryolTM 90, Solutol® HS-15 and Kollicoat® SR 30 D as non-volatile

586

liquid vehicles, Eur. J. Pharm. Biopharm. 83 (2013) 203–223.

TE D

584

[40] A. Sarkar, D. Ragab, S. Rohani, Polymorphism of Progesterone: A New Approach for

588

the Formation of Form II and the Relative Stabilities of Form I and Form II, Cryst.

589

Growth Des. 14 (2014) 4574–4582.

591 592 593 594 595

AC C

590

EP

587

[41] E. Albert, P. Andres, M.J. Bevill, J. Smit, J. Nelson, Cocrystals of progesterone, US20140235595 A1, 2014. http://www.google.com/patents/US20140235595. [42] M. EL-Badry, Preparation and characterization of albendzole microparticals prepared by freeze drying technique, Bull. Pharm. Sci. 31 (2008) 123–135. [43] A.S.A. Jabbar, A.A. Hussein, Formulation and evaluation of piroxicam liquisolid compacts, Int. J. Pharm. Pharm. Sci. 5 (2013) 132–141. 23

ACCEPTED MANUSCRIPT

596 597 598 599

RI PT

600 601 602

SC

603 604

Table 1: Formulation of liquisolid formulations each containing 50 mg of Progesterone

Drug concentration in liquid medication (%)

Carrier : Coat ratio

Liquid load factor (Lf)

LS-1

10

10

LS-2

15

10

LS-3

20

LS-5

Coat (mg)

SSG (8%)

Total weight (mg)

Molecular Fraction (Fm)

1.25

500

400.00

40.00

75.20

1015.20

0.8920

1.25

333

267.20

26.70

50.17

677.40

0.5947

1.25

250

200.00

20.00

37.60

507.60

0.4460

TE D

Carrier (mg)

10

AC C

LS-4

Liquid medication (mg)

EP

Liquisolid system

M AN U

605

25

10

1.25

200

160.00

16.00

30.08

406.08

0.3568

30

10

1.25

167

133.28

13.30

25.05

338.23

0.2974

606 607 24

ACCEPTED MANUSCRIPT

608 609 610 611

RI PT

612 613 614

SC

615 616

618

M AN U

617

Table 2: Flow properties of Progesterone liquisolid system Carr’s

Liquisolid

Angle of

system

repose (θ)

Hausner’s

Compressibility

ratio

LS-1 LS-2

32.56± 1.30

7.83 ±1.48

1.08 ±1.50

33.93 ±1.45

12.63 ±1.30

1.14 ±1.21

33.87 ±1.12

15.66 ±1.61

1.20 ±1.32

EP

LS-3

TE D

index (%)

620 621

35.79 ±1.67

20.00 ±1.31

1.25 ±1.65

LS-5

36.08 ±1.26

23.95 ±1.74

1.31 ±1.72

AC C

619

LS-4

All readings are average ± SD (n=3)

622 623 624 25

ACCEPTED MANUSCRIPT

625 626 627 628

RI PT

629 630 631

SC

632 633

635

M AN U

634

Table 3: Evaluation Data for Progesterone Liquisolid compacts Weight

Diameter

Thickness

(mm)

(mm)

Formulation

Disintegration

Hardness

Variation

Friability (%)

(Kg/cm2)

time (s)

TE D

(mg)

13.12 ± 0.11

5.11 ± 0.02

6.8

845.30 ±0.12

0.09 ± 0.02

63.65 ± 0.34

LS-2

13.13 ± 0.14

4.68 ± 0.01

6.3

567.00 ±0.08

0.13 ± 0.01

60.69 ± 0.50

LS-3

13.12 ± 0.34

4.28 ± 0.04

4.2

423.00 ±0.14

0.09 ± 0.01

50.44 ± 0.64

LS-4

13.13 ± 0.23

2.84 ± 0.03

3.5

337.00 ±0.47

0.07 ± 0.02

40.30 ± 0.15

LS-5

13.10± 0.15

2.08 ± 0.04

3.2

282.75 ±0.17

0.27 ± 0.02

36.07 ± 0.11

637 638

AC C

636

EP

LS-1

All readings are average ± SD (n=3)

639 640 641 26

ACCEPTED MANUSCRIPT

642 643 644 645

RI PT

646 647 648

SC

649 650

M AN U

651

Figure Captions List

652 653 654

Fig. 1. : Relationship between angle of slide and phi value for Syloid 244 FP and Neusilin US2

Fig. 2. : Schematic Representation of Mechanism of conversion of liquid to liquisolid system

656

Fig. 3. : SEM images (1000×) for A) drug; B) LS-1 and C) LS-5

657

Fig. 4. : FT-IR Spectra of liquisolid formulation (LS-1, LS-5), Physical Mixture,

660 661 662 663 664 665 666

EP

659

Progesterone and excipients.

Fig. 5. : X-ray diffractograms of liquisolid formulation (LS-1, LS-5), Physical Mixture, and Progesterone

AC C

658

TE D

655

Fig. 6. : Thermogram of liquisolid formulation (LS-1, LS-5), Physical Mixture, Progesterone and excipients.

Fig. 7. : Dissolution profile of Progesterone, Conventional tablet and Liquisolid system in water with 2% SLS Fig. 8. : Effect of various ratios of carrier to coat material (Neusilin US 2 to Syloid 244 FP) on dissolution profile of Progesterone liquisolid compacts. 27

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Fig. 9. : Dissolution profile of Fresh v/s Aged LS-1 tablets in Water + 2% SLS dissolution

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