SCIFED saturated solution. The thermodynamic activity of the pure solute measures the escaping...

Click here to load reader

download SCIFED saturated solution. The thermodynamic activity of the pure solute measures the escaping tendency

of 11

  • date post

    16-Jan-2020
  • Category

    Documents

  • view

    0
  • download

    0

Embed Size (px)

Transcript of SCIFED saturated solution. The thermodynamic activity of the pure solute measures the escaping...

  • page 1 of 11ISSN:XXXX-XXXX SFPJ, an open access journal

    Volume 1 · Issue 3 · 1000010SF Pharma J

    Research Article Open Access

    Publishers SCIFED

    SciFed Journal of Pharmaceutics Journal

    Himankar Baishya, SF Pharma J, 2018, 1:3

    Selection of Co-Solvent System for Injectable Dosage Form of an Antihyperparathyroid Drug using Statistical Design

    *Himankar Baishya, Manas Boxi, Zhang Zibin

    *Beijing Sciecure Pharmaceuticals, Zhongbei Industrial Park, Beishicao Town, Shunyi District, Beijing, P.R. China- 101301

    Keywords Paricalcitol Injection; Co-Solvent; Experimental Design; Drug Stability

    Introduction Out of newly discovered drugs more than 40% drugs are lipophilic and out of which up to 40% of pharmacologically active new molecules failed to reach market only due to little or no water solubility; a serious challenge for the successful development and commercialization of new drugs in the pharmaceutical industry [1]. Therefore various formulation strategies have been investigated to improve the solubility of lipophilic drugs which includes the use of co-solvents, surfactants, lipids, micronisation, salt formation, complexation using cyclodextrins, nanoparticulate formulation, solid dispersions, etc. The solubility of a compound depends upon the physical and chemical properties of the solute and solvent as well as on such factors as temperature, pressure, the pH of the solution, and also on the state of subdivision of the solute.

    The oral route remains the preferred route of drug administration due to its convenience, good patient compliance and low medicine production costs. However, many drug molecules need to be formulated in other routes due to either high degradation of the active moiety in the gastric environment, very poor absorption profile in the git, poor in-vitro-in-vivo correlation, faster onset of action

    *Corresponding author: Himankar Baishya, Beijing Sciecure Pharmaceuticals, Zhongbei Industrial Park, Beishicao Town, Shunyi District, Beijing, P.R. China- 101301. E-mail: himankar@sciecure.com

    Received July 11, 2018; Accepted August 05, 2018; Published August 17, 2018

    Citation: Himankar Baishya (2018) Selection of Co-Solvent System for Injectable Dosage Form of an Antihyperparathyroid Drug using Statistical Design. SF Pharma J 1:3. Copyright: © 2018 Himankar Baishya. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    Abstract The objective of this work was to evaluate the potential of various co-solvents for development of an injectable dosage form of Paricalcitol in a convenient as well as industrially feasible method. Paricalcitol is a potent molecule for prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease. It is marketed by Abbott Laboratories as Zemplar® in capsule as well as injectable dosage forms. We developed an injectable formulation of the same for intravenous drug delivery. pH solubility study of Paricalcitol reveals that it is insoluble at all pH values. Hence, co-solvency approach was undertaken for preparing a thermodynamically stable system with enhanced solubility. The prepared products were then analyzed for chemical stability. Experimental design was applied for selection of optimum co-solvent system as well as for prediction of the most desirable formula. The formulation design space is constructed in terms of drug stability in solution state and assay during long term and accelerated storage conditions. The selected formulation exhibited sufficient chemical stability upon storage for up to 6 months with no visible precipitation and acceptable potency.

    mailto:himankar%40sciecure.com?subject=

  • page 2 of 11ISSN:XXXX-XXXX SFPJ, an open access journal

    Volume 1 · Issue 3 · 1000010SF Pharma J

    Citation: Himankar Baishya (2018) Selection of Co-Solvent System for Injectable Dosage Form of an Antihyperparathyroid Drug using Statistical Design. SF Pharma J 1:3.

    needed or a combination of the above factors. Currently only 8% of new drug candidates have both high solubility and permeability [2]. Thus, one of the major challenges to drug development today is poor solubility, as an estimated 40% of all newly developed drugs are poorly soluble or insoluble in water. The solubility of a solute in a solvent is equal to the thermodynamic activity of the solute, usually in the pure state, divided by the activity coefficient of the solute in the saturated solution. The thermodynamic activity of the pure solute measures the escaping tendency of the solute from the pure state and decreases with increasing strengths of the solute-solute interactions, which for solid, is reflected in the melting point and lattice energy. Low solubility’s of many polar solids often results from their high melting points and high lattice energies. Modification of solid state such as the formation of amorphous forms, metastable polymorphs, co-crystals, or novel particles, cans abolish or lower the lattice energy and can therefore increase the solubility of a compound. The activity coefficient of the solute in the saturated solutions depends on the relative strengths (enthalpy) of the solute-solvent and solvent- solvent interactions and the degree of disordering (entropy) of the solvent molecules around the solute molecules [4]. The low solubility of many non-polar compounds in water result from the unfavourable negative entropy due to hydrocarbons group, known as the hydrophobic interaction. Many methods of solubility enhancement depend on the lowering the activity coefficient by means of ingenious strategies for enhancing the interactions in solutions [5]. Management of secondary hyperparathyroid has included the use of active vitamin D or vitamin D analogs for the suppression of parathyroid hormone (PTH) secretion. Although, these agents are effective, therapy is frequently limited by hypercalcemia, hyperphosphatemia, and/or eleva- vitamin D3), hypocalcemia, and hyperphosphatemia and/or elevations in the calcium-phosphorus (Ca-P) product [6]. Both oral and parenteral forms of calcitriol have been effective in treating and preventing secondary hyperparathyroidism. However, intravenous calcitriol has been more widely used and thought to be the more effective form [7]. We intend to develop an intravenous formulation of Paricalcitol for clinical management of secondary hyperparathyroidism.

    Materials and Methods Due to the hydrophobic nature of Paricalcitol, the

    main target during drug development stage was selection of appropriate parenteral excipients within acceptable limits for complete solubilization of the API and the resultant solution remain stable during storage during its shelf life. Co-solvency approach was undertaken so as to increase the solubility of Paricalcitol. Two critical parameters associated with drug solubility were identified: (i) Chemical stability of drug product in aqueous media (ii) Precipitation of Paricalcitol

    The obtained formulations were subjected to initial Freeze-Thaw studies for screening of appropriate co-solvent systems for Paricalcitol followed by stability studies at accelerated as well as normal conditions. Formulation development was started by using a co-solvent with similar properties as propylene glycol. Ethanol as the co-solvent was used in accordance with innovator product. In the initial trials, Glycerol 99.5% was used as the solubilizer. Furthur trials were taken using PEG 200, Polysorbate 80, PEG 300, PEG 400 and Macrogol esters. Statistical experimental design was used to obtain the co- solvent system with maximum desirability for the critical parameters. The formulation design space was constructed in terms of variability in concentration of co-solvent. (Table 1) Freeze Thaw study was carried out by subjecting the samples to alternating environments of 2-8ºC and 40ºC every 7 days. Samples were observed for presence / absence of precipitation of Paricalcitol or any other component of the formulation.

    Statistical Analysis The various parameters analyzed were subjected to statistical analysis using Design Expert Pro (Version 10). Statistical significance was determined by one-way ANOVA, with p

  • page 3 of 11ISSN:XXXX-XXXX SFPJ, an open access journal

    Volume 1 · Issue 3 · 1000010SF Pharma J

    Citation: Himankar Baishya (2018) Selection of Co-Solvent System for Injectable Dosage Form of an Antihyperparathyroid Drug using Statistical Design. SF Pharma J 1:3.

    Table 1: Composition of Paricalcitol Injection using Various Solubilizers

    Ingredients Composition (% v/v)

    Experiment 1 Experiment 2 Experiment 3 Experiment 4 Experiment 5 Experiment 6

    Paricalcitol 0.0005 0.0005 0.0005 0.0005 0.0005 0.0005

    Ethanol 20.00 20.00 20.00 20.00 20.00 20.00

    Glycerol 99.5% 15.00 --- --- --- --- ---

    PEG 200 --- 15.00 --- --- --- ---

    Polysorbate 80 --- --- 10.00 --- --- ---

    PEG 300 --- --- --- 15.00 --- ---

    PEG 400 --- --- --- --- 12.00 ---

    Macrogol 15 Hydroxystereate --- --- --- --- --- 0.50

    WFI Q.S. Q.S. Q.S. Q.S. Q.S. Q.S.

    studies. However, there occurs a steady decline in drug content during 3 months at accelerated and normal storage conditions.(Graph 1)

    ● Furthur trials were conducted using Polysorbate 80 as the solubilizing agent.