Role of valsartan as an anti-plasticizer in development of

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Role of valsartan as an anti-plasticizer in development of therapeutically viable drug-drug co amorphous system Anurag Lodagekar, Rahul B Chavan, Naveen Chella, and Nalini R. Shastri Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00081 • Publication Date (Web): 02 Mar 2018 Downloaded from http://pubs.acs.org on March 2, 2018

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Crystal Growth & Design

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Role of valsartan as an anti-plasticizer in development of therapeutically

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viable drug-drug co amorphous system

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Anurag Lodagekar, Rahul B Chavan, Naveen Chella, Nalini R Shastri*

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Solid State Pharmaceutical Research Group (SSPRG), Department of Pharmaceutics, National

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Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India

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*Corresponding author: Nalini R Shastri

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Tel. +91-040-23423749

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Fax. +91-040-23073751

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E-mail: [email protected],

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Address: Department of Pharmaceutics, National Institute of Pharmaceutical Education &

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Research (NIPER), Balanagar, Hyderabad, India, Pin code-500037

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ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Abstract

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In a rapidly growing field of co amorphous systems, selection of appropriate coformer is a

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challenging task, especially while developing drug-drug co amorphous system, as one of the

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component should possess glass forming potential, and the combination generated is required to

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be therapeutically active. The present study was hence aimed towards exploring the glass

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forming potential of valsartan for the development of therapeutically active drug-drug co

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amorphous system. Co amorphous system of valsartan-cilnidipine in 6 different weight ratios

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(4:1, 3:1, 2:1, 1:1, 1:2 and 1:3), along with the therapeutically relevant weight ratio (16:1) were

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prepared by quench cooling method and evaluated for anti-plasticization effect of valsartan using

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DSC/MDSC. Generated co amorphous systems were studied for their dissolution benefits and

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stability under accelerated conditions (40 ⁰C/ 75 % RH). DSC and FTIR outcome along with

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prediction of Tg of drug-drug mixture using Gordon-Taylor and Couchman–Karasz equation

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demonstrated that for the generation of co amorphous system, anti-plasticization activity of

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valsartan played a dominant role. Co amorphous system with higher valsartan content was found

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to provide significantly higher dissolution benefits and stability under accelerated conditions for

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1 month. This study may pave path for the development of valsartan based co amorphous system

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in the treatment of cardiovascular diseases.

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Keywords: cilnidipine, DSC, glass transition temperature, stability, dissolution

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Desired drug action or bioavailability, predominantly depends on solubility, permeability

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and potency. Except for potency, which is an intrinsic property, solubility and permeability are

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the dominant biopharmaceutical properties which play a key role in converting propitious new

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chemical entities (NCEs) into potential drug candidates.1 Numerous formulation approaches such

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as complexation,2 mesoporous drug delivery,3 nano formulations, and lipid based formulations4

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have been reported to tackle problems arising due to inadequate solubility or permeability. Solid

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state manipulation by micronization, crystal habit modification, polymorphism and

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amorphication1 are also employed to address the challenges in delivery of poorly soluble drugs.

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Apart from polymeric amorphous solid dispersion, co amorphous system, a new trending

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amorphous system has gained prominence in formulation strategy to improve the poor solubility

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of NCEs.5, 6 The term “co amorphous system” was coined by Chieng et al.,7 and was defined by

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Suresh et al., as “a multi-component single phase amorphous solid system which lacks

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periodicity in lattice and is associated by weak and discrete intermolecular interactions between

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the components”.8 One of the prime requirements while developing such multi component

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system is selection of suitable coformers which decides the fate of the formulation in terms of

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stability and performance.9 Selection process of coformers is very critical since the drug-drug

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combination generated should be pharmacological relevant and at least one drug should possess

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good glass forming ability. Because of this limitation, less than 25 drug-drug co amorphous

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systems have been reported to date.6

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Valsartan is known to have good glass forming ability due to its high glass transition

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temperature (Tg) i.e. 76 °C.10,

11

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coformer or as an anti-plasticizing agent for the development of drug-drug co amorphous

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systems remain unexplored. Clinical data reveals that, this cardiovascular drug is used in

To the best of our knowledge, potential of valsartan as a



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combination with other cardiovascular drugs such as simvastatin and cilnidipine to improve

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therapeutic efficacy.12, 13 Preliminary screening was conducted with valsartan - simvastatin and

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valsartan - cilnidipine combinations at different weight ratios. Valsartan and simvastatin co

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amorphous system at therapeutically relevant dose of 4:1 (160 mg: 40 mg) gave single phase

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amorphous system after quench cooling. However, during stability studies, the co amorphous

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material was transformed to a rubbery mass followed by recrystallization, as observed from the

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appearance of a melting endotherm of simvastatin at 140.4 ⁰C (supplementary figure S1). As a

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result, further studies on these systems were not performed. In contrast, valsartan and cilnidipine

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co amorphous system showed promising results on stability and were selected for further studies.

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The present project was embarked with an objective to explore the glass forming

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potential of valsartan for the development of therapeutically relevant drug-drug co amorphous

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systems with cilnidipine. Barring few examples; ezetimib-lovastatin14 and nateglinide-

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metformin15, most of the reported drug-drug co amorphous systems though therapeutically

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relevant, are usually generated in 1:1 weight or molar ratio, which are generally not in a

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therapeutically administered relevant dose combination. Ergo, such combination may not be

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useful for the development of final formulation, due to the possibility of sub therapeutic or toxic

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concentration of one or both drugs in plasma after administration. Valsartan- cilnidipine in a

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therapeutically relevant weight ratio (16:1) equivalent to 160 mg: 10 mg respectively lowered the

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blood pressure significantly when compared to plain valsartan and cilnidipine, as reported in

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ClinicalTrials.gov Identifier: NCT02343250 of U.S National library of medicine. The second

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objective of this study was hence to evaluate the stabilization potential of valsartan at the

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reported valsartan- cilnidipine fixed dose combinations. The anti-plasticization effect of

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valsartan was explained by Gordon Taylor (GT) and Couchman–Karasz (CK) models. The


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difference in the solubility parameter (ΔSP) of the drugs was determined to predict the

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miscibility of the binary system. The co amorphous systems were subjected to accelerated

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stability studies to evaluate the stabilization potential of valsartan.

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For determination of the heat capacity (Cp) and glass transition temperature (Tg),

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cilnidipine (Unique Chemicals, Mumbai, India) and valsartan (Lupin Pharmaceuticals, INC.

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Pune, India) were converted into amorphous form, in situ, using a Differential Scanning

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Calorimeter (Mettler Toledo DSC system equipped with STARe software). Approximately 5-15

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mg of the drugs were sealed in pinholed aluminum pans individually, heated at a rate of 10 °C /

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min up to 130 °C and immediately cooled to 10 ⁰C at a cooling rate of -20 ⁰C/min. Quench

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cooling method was used to prepare co amorphous systems of valsartan with cilnidipine in

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various weight ratios (1:3, 1:2, 1:1, 2:1, 3:1, 4:1 and 16:1). Prior to quench cooling, all binary

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blends were gently but thoroughly mixed to avoid the inconsistency in the blends with an aid of

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mortar and pestle for 2-5 min. This crystalline blend was melted in a stainless steel spatula over a

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hot plate (130 ⁰C) and quench cooled over a crushed ice bed. Since, moisture can impact the Tg,

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appropriate precautionary measures were taken during the experiments to avoid inadvertent

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contamination with moisture, such as use of moisture proof paraffin films wrapped around the

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spatula immediately before transferring it from hot plate to crushed ice. The cooled samples were

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kept in desiccators for 12 hr for removal of any adsorbed moisture. All ratios were prepared in

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triplicates to verify the reproducibility.

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Quench cooled products were assessed for chemical stability by a validated HPLC

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method. The samples were analyzed on a HPLC system (e2695 Waters) consisting of a HPLC

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pump, an automated injector equipped with a Photo Diode detector (2998 PDA) and an auto

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sampler. Details of the HPLC method used are given in supporting information table S1. The



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peak purity was calculated based on the purity angle and purity threshold values of the

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chromatogram for the eluted drug; the peak was considered as pure peak when the purity angle

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was less than the purity threshold. All quench cooled samples were chemically stable and gave

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peak purity above 99.99%. Thermal characterization of the generated co amorphous systems was

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carried out using DSC. All seven valsartan: cilnidipine in weight ratio showed a single Tg values

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indicating the formation of a single phase, co amorphous system. Tg values for the ratios studied

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lie between 31 °C to 76 °C. (figure 1 and supplementary table S2). The Tg values of the

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experimentally prepared quench cooled systems were statistically similar (p> 0.05) to the Tg

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values of in situ generated co amorphous systems using DSC (supplementary figure S2 and table

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S2).

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Figure 1 DSC curves of quench cooled cilnidipine (CLD), valsartan (VAL) and VAL-CLD co amorphous systems. Arrow indicates the average of three Tg values.


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To further confirm the amorphous nature of the quench cooled samples, powder XRD

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(PXRD) patterns of the individual crystalline and amorphous forms of drugs with their physical

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mixture and binary blends were recorded on Bruker D8 Advance diffractometer (Bruker- AXS,

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Karlsruhe, Germany) with Cu-Kα X-radiation (λ= 1.5406 Å) at 2θ range 5–50° with a step time

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of 0.030 steps/0.5 s. Crystalline cilnidipine exhibited its characteristic 2θ values at 5.7, 11.65,

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12.19, 14.17, 16.35, 18.63, 19.76 and 21.65 corresponding to the reported literature values16

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(figure 2). However, crystalline valsartan did not show any Bragg’s peaks probably due to its

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smaller particle size (less than 0.1 µm) and its mesophasic nature wherein the long range-order

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of the stable crystal is limited to length of tens of nanometer scale.17 The crystallinity of

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valsartan was however confirmed by DSC (supplementary figure S3) and hot stage microscopy

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(data not shown). The quench cooled samples with halo pattern and an absence of Bragg’s peaks

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in PXRD analysis confirmed the amorphous nature of the samples, supporting the findings of

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DSC.

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Figure 2 PXRD overlay of co amorphous valsartan (VAL): cilnidipine (CLD) in different weight ratios



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FTIR spectra were used to detect the presence of intra/inter molecular interactions

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between valsartan and cilnidipine in quench cooled samples. The spectra were recorded on

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PerkinElmer FTIR C95065 spectrophotometer operating with Spectrum software in the region of

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500-4000 cm-1. FTIR analysis revealed an absence of intermolecular interactions between these

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two drugs in quench cooled samples (figure 3). Taken collectively, the DSC, PXRD and FTIR

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results suggested that quench cooled samples of cilnidipine were present in amorphous form with

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valsartan at all weight ratios.

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Figure 3 FT-IR Spectra of crystalline (a) and amorphous (b) cilnidipine, amorphous (c) and crystalline (d) valsartan, crystalline (e) and amorphous (f) physical mixture of valsartan and cilnidipine (16:1), and their co amorphous systems in different weight ratios (h) 1:3, (i) 1:2, (j) 1:1, (h) 2:1, (k) 3:1, (i) 4:1, (m) 16:1.

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Prediction of Tg of values of valsartan: cilnidipine mixture using Gordon- Taylor (GT)

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equation and Couchman–Karasz (CK) equation were performed to obtain insights on the

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mechanism by which valsartan stabilizes the co amorphous systems. This study helps in


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assessing whether intermolecular interactions or anti plasticization effect of valsartan play an

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important role in stabilization. The GT equation is based on the additivity of free volumes of the

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individual components characteristic of ideal mixing. The equation helps in estimating the

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theoretical Tg of a co amorphous system as a function of composition. The GT equation reads as: ܶ௚௠௜௫ =

‫ݓ‬ଵ ∗ ܶ௚ଵ + ‫ݓ ∗ ்ீܭ‬ଶ ∗ ܶ௚ଶ ‫ݓ‬ଵ + ‫ݓ ∗ ்ீܭ‬ଶ

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Where w1 and w2 are the weight fraction of each component, Tg1 and Tg2 are the Tg of each

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component (wherein Tg1 ≤ Tg2). KGT is the ratio of the free volumes of individual components

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and is calculated by ‫= ்ீܭ‬

ߩଵ ∗ ∆ߙଵ ߩଵ ∗ ܶ௚ଵ ≈ ߩଶ ∗ ∆ߙଶ ߩଶ ∗ ܶ௚ଶ

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Where ρ, Tg and ∆α are, respectively, the density, the Tg, and the change in the thermal

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expansivities of each component at the respective Tgs. The Tg values of in situ quench cooled

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cilnidipine and valsartan generated using MDSC were found to be 23.36 ⁰C and 76.25 ⁰C,

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respectively, while, the true density values for cilnidipine and valsartan were found to be 1.24

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and 1.2 g/ml, respectively.

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CK equation results from the expression of total molar entropy of the blend and reads as, ln ܶ௚ =

‫ݔ‬ଵ ∗ ln ܶ௚ଵ + ‫ܭ‬஼௄ ∗ ሺ1 − ‫ݔ‬ଵ ሻ ∗ ܶ௚ଶ ‫ݔ‬ଵ + ‫ܭ‬஼௄ ∗ ሺ1 − ‫ݔ‬ଵ ሻ ‫ܭ‬஼௄ =

∆‫ܥ‬௣ଶ ∆‫ܥ‬௣ଵ

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Where, ∆Cp1 and ∆Cp2 are the changes in specific heat capacity of each component at their

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respective Tgs. The Cp1 (cilnidipine) and Cp2 (valsartan) generated from MDSC experiments were

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found to be 0.359 and 0.48 J/g, respectively.



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For a co amorphous system, Tg can be accurately predicted by GT equation, which

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suggest whether two components mix ideally and are fully miscible at molecular level. Deviation

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of experimental Tg values from the theoretical values indicate strong inter molecular interactions

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and non ideal mixing.18 At lower ratios, no significant deviation was observed between the

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experimental Tg and the Tg obtained from the GT and CK model fit as determined from the slope

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and coefficient comparisons. However, significant deviation was observed at higher valsartan:

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cilnidipine weight ratio i.e. 4:1 and 16:1, which indicated an absence of intermolecular

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interactions between valsartan and cilnidipine in glass formation (figure 4). This deviation might

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be due to the contribution of the steric hindrance along with anti-plasticization effect.19

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Figure 4 Compositional variation of the Tg of co amorphous systems (a) Gordon Taylor (GT) and (b) Couchman–Karasz (CK) equations

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The findings from GT and CK curve fitting, the absence of molecular interaction in the

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quench cooled samples, coupled with high Tg values of valsartan suggested anti-plasticization

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effect of valsartan to be a dominating factor in generation and stabilization of co amorphous

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systems.20 With higher molar ratio of valsartan, the co amorphous system gave Tg values near to

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Tg value of valsartan demonstrating a direct correlation between the Tg values of the co


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amorphous systems generated and the amount of valsartan present in the systems. Additionally,

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the solubility parameter values for valsartan and cilnidipine were predicted using Materials

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Studio 7.0 (Accelrys Inc., USA) software. Solubility parameters for valsartan and cilnidipine

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were found to be 21.903 and 21.096, respectively. Minimal difference between the solubility

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parameter indicates that both components are miscible with each other.21, 22 Miscibility of the

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components in a blended system is of prime importance for the stabilization of an amorphous

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system, since it is generally believed that miscibility at molecular level is necessary to achieve

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maximum physical stabilization.

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Co amorphous systems are known to elicit and prolong the supersaturated solution state,

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hence in vitro dissolution study was conducted for all seven weight ratios of co amorphous

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systems in USP type II apparatus under non sink condition and compared with crystalline

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cilnidipine, amorphous cilnidipine and crystalline physical mixture of valsartan and cilnidipine in

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16:1 weight ratio. All samples were passed through sieve number ASTM #44 prior to the sample

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addition into the discriminating dissolution medium (6.8 pH buffer with 0.4% SLS) to maintain

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uniform particle size for all samples. Dissolution samples were analyzed using the above

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mentioned HPLC method. Peak purity was determined to ascertain the purity of each eluted

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component. DE15 (dissolution efficiency at 15 min) and f2 (similarity factor) values were

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calculated using DDsolver23 to compare the dissolution profiles.

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Plain crystalline cilnidipine showed only 27.53 % release in 120 min (figure 5). The

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cilnidipine release from physical mixture was found to be similar to crystalline cilnidipine (f2=

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60.71) as only 24.78 % of cilnidipine was released in 120 min (supplementary figure S4).

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However, cilnidipine release from the co amorphous systems was enhanced compared to its

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crystalline counterpart. Similarly, cilnidipine release showed an increment as the concentration



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of valsartan was increased in the co amorphous systems. Within 30 min, 100 % of cilnidipine

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was released from valsartan: cilnidipine co amorphous system in 16:1 ratio. The release patterns

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of other valsartan: cilnidipine co amorphous systems (4:1, 3:1, 2:1 and 1:1) were between the

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release pattern of 16:1 ratio and crystalline cilnidipine. The cilnidipine release from the 16:1

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valsartan: cilnidipine co amorphous system was 21 times more that the drug release from

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crystalline cilnidipine as seen from the DE15 value (Supplementary table S3). This significant

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enhancement in the drug release was attributed to the existence of cilnidipine as a co amorphous

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system with valsartan. No drug release was recorded from amorphous cilnidipine as it became

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rubbery immediately after preparation due to its low Tg value. Similarly, valsartan: cilnidipine at

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1:2 and 1:3 weight ratios also developed a rubbery state and failed to release the drug during the

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dissolution study. 120 100 % drug release

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80 60 40 20 0 0

20

CLD

226 227 228

VAL:CLD 3:1

40

60 Time (min) VAL:CLD 1:1

80

VAL:CLD 4:1

100

120

VAL:CLD 2:1 VAL:CLD 16:1

Figure 5 Release profiles of cilnidipine from crystalline cilnidipine (CLD) and its co amorphous systems with valsartan (VAL) in different weight ratios

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Drug release of valsartan from its crystalline and amorphous systems (figure 6) was

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found to be similar (f2 = 90.34). This can be attributed to the microcrystalline nature of valsartan

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in its crystalline counterpart. The release from lower ratios was not significantly different to

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crystalline and amorphous valsartan, as reflected by the similarity factor f2 >50 (supplementary

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table S4). Valsartan release from co amorphous systems at 16:1 weight ratios was more when

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compared to crystalline and amorphous valsartan. The amount of valsartan released from 16:1

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formulation nearly doubled at the end of 90 min when compared to crystalline valsartan.

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However, the enhancement in the release was not as significant as that observed with cilnidipine

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release, indicating that cilnidipine did not have a major impact on the dissolution of valsartan. 50

40

% Drug release

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30

20

10

0 0

239 240 241

20

40

60 Time (min)

80

C VAL

A VAL

VAL:CLD 1:1

VAL:CLD 3:1

VAL:CLD 4:1

VAL:CLD 16:1

100

120

VAL:CLD 2:1

Figure 6 Release profiles of valsartan from crystalline valsartan (CVAL), amorphous VAL (AVAL) and its co amorphous systems with cilnidipine (CLD) in different weight ratios

242 243

The stability of the generated co amorphous samples were evaluated by placing the

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samples in open and closed containers in a stability chamber (Osworld OPSH-G-16-GMP series,

245

Osworld Scientific Equipments Pvt. Ltd., India) at 40 ⁰C ± 2 ⁰C and 75 ± 5% relative humidity



246

(RH). Samples were withdrawn at specified period (0, 1, 2, 3 and 4 week) and analyzed by DSC

247

for monitoring the crystallinity. Additionally, at the end of the stability period, the stable

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formulations and the therapeutically relevant valsartan: cilnidipine ratio 16:1 was subjected to

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dissolution studies. As mentioned earlier, amorphous cilnidipine became rubbery immediately

250

after preparation and crystallized within first week on stability studies. Similarly, co amorphous

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systems with higher cilnidipine content (1:2 and 1:3) also crystallized under stability conditions.

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Melting endotherms in DSC analysis of the stability samples of these two weight ratios confirm

253

the instability (supplementary figure S5). Whereas, co amorphous valsartan: cilnidipine with

254

higher valsartan content (1:1, 2:1, 3:1, 4:1 and 16:1) were found to be stable for 1 month of

255

storage, as the respective samples did not show any melting endotherm of either drug in DSC

256

(figure S6). Evidence of amorphous nature was also confirmed by cross polarized microscopy by

257

absence of birefringence (data not shown). Valsartan: cilnidipine 16:1 co amorphous system on

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storage at the end of four week period showed similar dissolution profile (supplementary figure

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S7) as that of the freshly prepared co amorphous system (similarity factor value f2=62.14).

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Valsartan is an old drug and is extensively studied for its thermal behavior. However, its

261

potential in formation of co amorphous system has remained unexplored. Use of valsartan for the

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development of therapeutically active valsartan: cilnidipine co amorphous system was

263

demonstrated successfully in this present study. Outcome of the DSC and PXRD confirmed the

264

formation of co amorphous system by quench cooling method. Theoretical Tg prediction of

265

valsartan- cilnidipine mixture using GT and CK equation and FTIR demonstrated that anti

266

plasticization effect of valsartan was prevalent in formation of co amorphous system. Evaluation

267

of the generated co amorphous systems with higher valsartan content was stable for 1 month

268

under accelerated stability conditions. Similarly, compared to crystalline cilnidipine, nearly 5


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fold enhancement in the dissolution at end of 2 h, was observed with valsartan: cilnidipine co

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amorphous system at 16:1 weight ratio (which is the therapeutically active dose ratio). This

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preliminary study on potential of valsartan as a coformer in the development of co amorphous

272

system may pave path for more therapeutically active drug-drug co amorphous system. Clinical

273

data has demonstrated that administration of valsartan cilnidipine combination in 16:1 ratio

274

provides maximum benefits in lowering the blood pressure. Development of co amorphous

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system at the same ratio may thus help in achieving the same therapeutic benefits.

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Supporting information

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DSC thermograms of stability samples, in situ quench cooled systems, crystalline drugs.

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Dissolution profile of stability samples, Chromatographic parameters for HPLC analysis, Glass

279

transition temperatures, Comparison of drug release.

280

Acknowledgement

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The authors acknowledge the financial support from the Department of Pharmaceuticals (DoP),

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Ministry of Chemicals and Fertilizers, Govt. of India.

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Conflict of interest

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The authors declare no competing financial interest.

285

References

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(1) Kaushal, A. M.; Gupta, P.; Bansal, A. K., Amorphous drug delivery systems: molecular aspects, design, and performance. Crit Rev Ther Drug Carrier Syst 2004, 21, 133–193. (2) Szabó, Z.-I.; Gál, R.; Gáll, Z.; Vancea, S.; Rédai, E.; Fülöp, I.; Sipos, E.; Donáth-Nagy, G.; Noszál, B.; Tóth, G., Cyclodextrin complexation improves aqueous solubility of the antiepileptic drug, rufinamide: solution and solid state characterization of compound-cyclodextrin binary systems. J Incl Phenom Macrocycl Chem 2017, 88, 43-52. (3) Wang, S., Ordered mesoporous materials for drug delivery. Microporous Mesoporous Mater 2009, 117, 1-9. (4) Porter, C. J.; Pouton, C. W.; Cuine, J. F.; Charman, W. N., Enhancing intestinal drug solubilisation using lipid-based delivery systems. Adv Drug Deliv Rev 2008, 60, 673-691. (5) Dengale, S. J.; Ranjan, O. P.; Hussen, S. S.; Krishna, B.; Musmade, P. B.; Shenoy, G. G.; Bhat, K., Preparation and characterization of co-amorphous Ritonavir–Indomethacin systems by solvent



298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343

evaporation technique: Improved dissolution behavior and physical stability without evidence of intermolecular interactions. Eur J Pharm Sci 2014, 62, 57-64. (6) Chavan, R. B.; Thipparaboina, R.; Kumar, D.; Shastri, N. R., Co amorphous systems: A product development perspective. Int J Pharm 2016, 515, 403-415. (7) Chieng, N.; Aaltonen, J.; Saville, D.; Rades, T., Physical characterization and stability of amorphous indomethacin and ranitidine hydrochloride binary systems prepared by mechanical activation. Eur. J. Pharm. Biopharm. 2009, 71, 47-54. (8) Suresh, K.; Mannava, M. C.; Nangia, A., A novel curcumin–artemisinin coamorphous solid: physical properties and pharmacokinetic profile. RSC Adv 2014, 4, 58357-58361. (9) Korhonen, O.; Pajula, K.; Laitinen, R., Rational excipient selection for co-amorphous formulations. Expert Opin Drug Deliv 2017, 14, 551-569. (10) Wang, J.-R.; Wang, X.; Lu, L.; Mei, X., Highly crystalline forms of valsartan with superior physicochemical stability. Cryst Growth Des 2013, 13, 3261-3269. (11) Ramos, J. J. M.; Diogo, H. P., Thermal behavior and molecular mobility in the glassy state of three anti-hypertensive pharmaceutical ingredients. RSC Adv 2017, 7, 10831-10840. (12) Takai, S.; Jin, D.; Aritomi, S.; Niinuma, K.; Miyazaki, M., Powerful vascular protection by combining cilnidipine with valsartan in stroke-prone, spontaneously hypertensive rats. Hypertens Res 2013, 36, 342–348. (13) Nagasawa, K.; Takahashi, K.; Matsuura, N.; Takatsu, M.; Hattori, T.; Watanabe, S.; Harada, E.; Niinuma, K.; Murohara, T.; Nagata, K., Comparative effects of valsartan in combination with cilnidipine or amlodipine on cardiac remodeling and diastolic dysfunction in Dahl salt-sensitive rats. Hypertens Res 2015, 38, 39-47. (14) Riekes, M. K.; Engelen, A.; Appeltans, B.; Rombaut, P.; Stulzer, H. K.; Van den Mooter, G., New perspectives for fixed dose combinations of poorly water-soluble compounds: a case study with ezetimibe and lovastatin. Pharm Res 2016, 33, 1259-1275. (15) Wairkar, S.; Gaud, R., Co-amorphous combination of nateglinide-metformin hydrochloride for dissolution enhancement. AAPS PharmSciTech 2016, 17, 673-681. (16) Hu, L.; Song, W.; Niu, F.; Jiao, K.; Jia, Z., Preparation, characterization and tableting of cilnidipine solid dispersions. Pak J Pharm Sci 2013, 26, 629-636. (17) Guinet, Y.; Paccou, L.; Danède, F.; Derollez, P.; Hédoux, A., Structural description of the marketed form of valsartan: A crystalline mesophase characterized by nanocrystals and conformational disorder. Int J Pharm 2017, 526, 209-216. (18) Kini, A.; Patel, S. B., Phase behavior, intermolecular interaction, and solid state characterization of amorphous solid dispersion of Febuxostat. Pharm Dev Technol 2017, 22, 45-57. (19) Knapik, J.; Wojnarowska, Z.; Grzybowska, K.; Tajber, L.; Mesallati, H.; Paluch, K. J.; Paluch, M., Molecular dynamics and physical stability of amorphous nimesulide drug and its binary drug–polymer systems. Mol Pharm 2016, 13, 1937-1946. (20) Knapik, J.; Wojnarowska, Z.; Grzybowska, K.; Jurkiewicz, K.; Tajber, L.; Paluch, M., Molecular dynamics and physical stability of coamorphous ezetimib and indapamide mixtures. Mol Pharm 2015, 12, 3610-3619. (21) Fedors, R. F., A method for estimating both the solubility parameters and molar volumes of liquids. Polym Eng Sci 1974, 14, 147-154. (22) Ilevbare, G. A.; Liu, H.; Edgar, K. J.; Taylor, L. S., Maintaining supersaturation in aqueous drug solutions: Impact of different polymers on induction times. Cryst Growth Des 2012, 13, 740-751. (23) Zhang, Y.; Huo, M.; Zhou, J.; Zou, A.; Li, W.; Yao, C.; Xie, S., DDSolver: an add-in program for modeling and comparison of drug dissolution profiles. AAPS J 2010, 12, 263-271.

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Role of valsartan as an anti-plasticizer in development of therapeutically viable drug-drug co amorphous system Anurag Lodagekar, Rahul B Chavan, Naveen Chella, Nalini R Shastri

Table of Content Graphic

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Synopsis

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Anti-plasticization potential of valsartan was explored for the first time in development of

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therapeutically active drug-drug co amorphous system with cilnidipine. The therapeutically

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administered relevant dose combination of valsartan: cilnidipine (16:1) was stable for 1 month

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under accelerated stability conditions (40 ⁰C/ 75 % RH) and showed 5 fold improvement in

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release of cilnidipine.


Role of valsartan as an anti-plasticizer in development of

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