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Introduction

Modulation and optimization of pharmaceutical formu-

lation, regardless the route of administration, is based on

the preformulation studies. for many metal complexes, their

low solubility in water or other biocompatible vehicles is the

critical factor in formulation. So far, different solubilization

techniques were studied and used for medicinal substances

poorly soluble in water. in this study we analyzed several

ways to increase the solubility of a new complex with anti-

tumor action, with general formula RuCl3(enrofloxacin)

2(DM

SO)0.5

(H2O) (RuE) by means of different co-solvent systems.

We studied the influence of co-solvent type, the influence of

pH on solubility, the stability of test solutions obtained with

appropriate co-solvent mixtures.

the optimum solubilization models were used for design-

ing biocompatible solvent systems, for allowing the complex

to be incorporated in topical hydrogel formulations. The in-

fluence of the solubilization system on the release kinetics of

RuE from the hydrogels was studied.

Materials and Methods

Materials:

Dioxan, DMSO, PEG 400, all of all of analytical grade, were

purchased from Merck. The HPLC grade ethanol was ob-tained from Sigma Aldrich.

Methods:

For determination of the RuE complex solubility, the

shake-flask method was applied: 10 ml of each co-solvent

system to an excess of drug substance, using 10 ml volumet-

ric flasks (all determinations were performed in triplicate).

The vials were vigorously mixed for 30 seconds, and main-

tained under sonication for 30 minutes, at 30C, by means

of a SonoSwiss thermostated ultrasonic bath. The samples

were placed for 24 hour on a Heidolph Vibramax 100 stirer.

The samples were furthemore centrifuged and the super-

natant was filtered throgh a celulose-esther membrane with

the average pore size 0,45 m. Spectrophotometric methods

were implemented for quantitative evaluations of drug dis-

solved, with calibration probes prepared in methanol and

processed blank media as reference. Quantitative determi-

nations were made at = 280 nm.

Mechanism of co-solvent solubilisation is interpreted by

the high capacity of these fluids to form multiple intermole-

cular hydrogen bonds between molecules of the same kind

and with molecules of different nature. in practice, to appro-

ximate solubility of compounds in co-solvent is used thetheory to take account of dielectric requirements. Accor-

ding to this theory, any solute has a maximum solubility in

a given solvent mixture, with one or more specific dielectric

constant.

Solubility of RuE in different water:dioxane mixtures was

evaluated and the dielectric constant for the optimum solu-

bilizing mixture was established.

Different biocompatible solvent systems (PEG 400, pro-pylene glycol, ethanol, water) with the same dielectric con-

stant were prepared and used for preparing hydrogels with

1% or 2% CMCNa.

The release kinetics of RuE from the hydrogels was studied

on a Hanson Microette system (Hanson Research Inc., USA)

with 12 ml vertical diffusion cells, by using water:propylene

glycol 1:1 v:v, receptor media

P 55Preformulation Studies for Incorporating of a New Ruthenium(III) Complex with Enrofloxacin in Topical FomulationsB. S. Velescu1, V. Anuta1, C. Dinu-Prvu1,2, V. Uivaroi11University of Medicine and Pharmacy, Carol Davila, Faculty of Pharmacy,Bucharest, Romania

2University Politehnica of Bucharest, Bucharest, Romania.

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Results and Discutions

The results are presented in the next tables and figures:

Table 1. Solubility of RuE in different water:dioxane mix-

tures

H2O:dioxane (v:v)

apSolubility

(mg/mL)

3 1 73.27 0.59

2 2 64.61 0.96

1 3 48.43 0.97

1 9 28.12 0.71

9 1 76.36 0.08

In fig 1 is represented the variation of solubility with the

value ofap

Fig 1 the variation of solubility with the value ofap

The pH and experimental conditions influence on RuE

solubility is presented in table 2 and fig 2.

Table 2 pH influence on RuE solubility

pHS

(mg/ml)

1.46 0.017

5.00 0.016

7.08 0.019

8.12 0.400

10.40 0.700

11.92 1.210

Fig. 2. Experimental conditions influence on RuE solubility

The influence of certain experimental parameters on

the solubility of the studied complex was evaluated. It was

found that the solubility depends on pH, having the higher

values in basic medium, due to the formation of sodium salt.

Although the value of solubility in basic medium is suitable

for pharmaceutical formulation process should still verify

the maintaining of a therapeutic effect comparable to that

of neutral complex (often forming a salt reduces / cancels

therapeutic effect).

Various co-solvent biocompatible systems used for solu-

bilization of RuE are presented in tables 3-5

Table 3. Water: propylene glycol systems used for solu-

bilization of RuE

H2O(mL)

Propyleneglycol (mL)

S(mg/mL)

3.8 6.2 64.61 0.89

1.4 9.6 48.43 0.91

Table 4Water: PEG 400 system used for solubilization of RuE

H2O(mL)

PEG 400(mL)

S(mg/mL)

1.5 23.5 48.43 0.99

Table.5 Water: propylene glycol: ethanol system used for

solubilization of RuE

H2O(mL)

Propyleneglycol (mL)

Ethanol(mL)

S(mg/mL)

5 10 10 51.76 0.84

The results shown that the solubility is almost identical to

that in water:dioxane of the same dielectric constant.

A representative result following the release kinetics of

RuE from 1% CMCNa hydrogel is presented in figure 3.

Fig. 3. Higuchi kinetic profile pethe diffusion of RuE in the

receptor media

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The in vitro drug release rates range is highly dependent

on viscosity, and increasing almost linearly with the concen-

tration of cellulose derivatives.

Conclusions

Studies have shown a significant improvement in solubil-

ity of Ru(III) enrofloxacin complex (approximately 30 times

using three different co-solvent systems) with co-solvent

solubilization method, which allowed us to select a biocom-

patible system useful for further pharmaceutical formulation

studies. The influence of certain experimental parameters on

the solubility of the studied complex was evaluated. It was

found that the solubility depends on pH, having the higher

values in basic medium, due to the formation of sodium salt.

Although the value of solubility in basic medium is suitable

for pharmaceutical formulation process should still verify

the maintaining of a therapeutic effect comparable to that

of neutral complex (often forming a salt reduces / cancels

therapeutic effect).

The solubility value is influenced by sonication, sonica-

tion temperature, type and time of stirring. The complex has

proved to be stable in the biocompatible systems proposed,

providing real benefits in future formulation processes (re-

gardless the route of administration chosen).

Acknowledgements

This work was supported by the Grant Development

of systems with improved solubility for new ruthenium (lll)

complexes with quinolone antibiotics and testing their an-

ticancer activity of the Romanian Ministry of Education and

Research, Capacities Programme, Module III

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