Page 1 of 59
`
`CFAD V. Insys
`IPR2015-01799
`
`Page 1 of 59
`
`Insys Exhibit 2010
`CFAD v. Insys
`IPR2015-01799
`
`

`
`PHARMACEUTICAL
`
`
`
`
`
`TECHNOLOGY
`
`Volume I
`
`
`
`
`
`
`
`
`
`RSR Murthy
`
`
`
`
`
`Director and Head, Department of Pharmaceutics,
`
`
`
`ISF College of Pharmacy,
`
`
`Moga (Punjab)
`Former
`
`
`
`
`
`
`Professor, Govt. College of Pharmacy, Bangalore
`
`
`
`
`
`Professor, College of Pharmacy, New Delhi (DIPS-AR)
`
`
`
`
`
`
`Professor, The MS University of Baroda
`
`
`Ashutosh Kar
`Former
`
`
`
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`
`
`Professor, School of Pharmacy, Addis Ababa University
`
`
`
`Addis Ababa (Ethiopia)
`
`
`
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`
`
`Dean, Chairman & Professor, Faculty of Pharmaceutical Sciences
`
`
`
`
`
`Guru Jambheshwar University, Hisar (India)
`
`
`
`
`
`Professor, School of Pharmacy, Al-Arab Medical University
`
`
`Benghazi (Libya)
`
`
`
`
`
`
`Professor, College of Pharmacy, University of Delhi
`
`
`
`Delhi (India)
`'
`
`Professor & Head, Department of Pharmaceutical Chemistry
`
`
`
`
`
`Faculty of Pharniaceutical Sciences, University of Nigeria
`
`
`
`
`
`
`Nsukka (Nigeria)
`
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`_
`,
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`Notice: Medical Knowledge is constantly changing. As new research and clinical experience broaden our knowledge,
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`Work. They are also advised to verify the recommended dose, the method and duration of adniinistration and
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`contraindication. The authors and publishers do not assume any liability for anyinjury andfor damage to persons or
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`Copyright © 2013, New Age International (P) Ltd., Publishers
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`Published by New Age International (P) Ltd., Publishers
`First Edition: 2013
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`Page 3 of 59
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`

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`CONTENTS AT A_ "GLANCE
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`1._ LIQUID DOSAGE FORMS
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`.
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`.
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`introduction
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`. Formulations of"Liquids
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`Manufacturing of Liquid Products
`Packaging of Liquid Oral Products
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`.' Quality Assurance and Process Validation of Liquid Orais
`'M-anufacturingiCiiaiienges with Liquid C_)ra[s
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`Reférences. - 3
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`Page 4 of 59
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`' PI-iARMAcEuricAi. Tscniiotoev
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`vehicle, solubilizer, stabilizer, and viscosity builder, preservative and off
`course sweeteners, colour and flavour. The selection of these excipients
`is of major concern to design stable, effective and palatable oral liquid
`formulation.
`
`Selection of Excipients
`
`Characteristics of active drug are of major concern in developing an oral
`liquid dosage formulation. The major challenges in developing oral liquid
`dosage forms are
`
`(1) The stability of a drug in solution,
`
`(ii) The solubility of a drug at the required level, and
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`(iiz) An acceptable taste.
`
`It is the effective use of excipients, which allows formulators overcome
`thesechallenges. Additionally, an excipient’s compatibility withTdrug
`in the solid state cannot infer the same compatibility in solution. However,
`if the mechanism of degradation of the drug is understood, the process
`of selecting suitable excipients to use in a solution will be much easier.
`Finally, some knowledge of the drug's physical and chemical
`characteristics such as the solubility, pH stability,- and pKa value (_s) of
`reactive functional groups is essential in order to choose the proper
`excipients, effectively
`’
`
`Ideally, the pH at which the drug is most stable would also be close
`enough to the solubility for delivering the desired dose in a tea spoon
`(approximately 5 mL). Requiring patients to take more than two tea a
`spoon full at a time may not be advisable because of lower patient
`compliance. In such conditions, a simple oral solution or syrup
`formulation may be developed. However, if the pH at which the drug
`is most stable is not one at which there is enough solubility, a suspension
`formulation may be required.
`A quick means to identify whether or not a drug may be more
`suitable for solution or suspension is to overlap the pH-stability profile
`with the pH-solubility profile. This overlap creates a window, which
`may suggest which dosage form might be most desirable and
`subsequently the type of excipients needed. The overlapped figures below
`demonstrate for aspirin (which is a weak acid) that the pH of greatest
`stability is also the pH at which there is low solubility (Figure 1.1).
`5
`
`A quick means to identify
`whether or not a dmg may
`be more suitable for solution
`or suspension is to overlap
`the pH-stability profile with
`the pH-solubility profile.
`
`
`
`pKapH
`
`024631012’
`pH
`
`fig. 1.1. pH, Solubility and Stability Relationship
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`Page 6 of 59
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`iiouio. DOSAGE‘ Foiius V
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`The decision to develop a solution, syrup or a suspension of a drug
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`is influenced by many factors like solubility and the desired release
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`profile of the drug and properties of the base vehicle like surface tension,
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`viscosity, boiling point, and specific heat of solution, all of which may be
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`affected in various Ways. In case of clear liquids, lack of solubility of the
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`drug in the base vehicle may demand the need for miscible co-solvents.
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`Similarly, a miscible solvent may be needed to decrease the solubility of
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`the drug in a primary vehicle in formulating a suspension. Another
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`approach to increasing the solubility of a drug in solution is to use a
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`complexing agent such as a cyclodextrin. Currently in the United States,
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`only hydroxypropyl—B—cyclodextrin has been used in an oral liquid
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`formulation. However, many other cyclodextrins are Widely used outside
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`the United States in both oral and parenteral formulations. Surfactants
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`are also used to increase aqueous solubility of the drugs.
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`Eiccipients for Oral Liquid Formulationsz
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`Oral liquid formulation needs a meticulous blend of ingredients to
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`perform various functions like wetting and solubilisation, stabilization
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`and to impart suitable colour, taste and viscosity. The blend should be
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`compatible, non reactive and stable. The common excipients generally
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`required for any liquid formulation are Vehicles (base), Viscosity builders,
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`' stabilizers, preservatives, colours and flavours. In addition, solubilizers
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`are required in ‘case of clear liquids, suspending agents are needed for ’
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`suspensions and emulsifying agents for emulsions.
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`Oral liquid formulation —
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`needs a meticulous blend of
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`ingredients
`to perform
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`various functions like wetting
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`solubllisation,
`and
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`stabilization and to impart
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`suitable colour,
`taste and
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`viscosity.
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`if
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`\{e,l1ic,:|_es
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`Vehicles, in pharmaceutical formulations, are the liquid bases that carry
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`drugs and other excipients in dissolved or dispersed state. Pharmaceutical
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`vehicles can be classified as under;
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`Aqueous vehicles: V\later, hydro—a1coholic, polyhydric alcohols and buffers.
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`These may be thin liquids, thick syrupy liquids, mucillages or
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`hydrocolloidal bases.
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`Oily vehicles: Vegetable oils, mineral oils, organic oily bases or emulsified
`bases.
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`Aqueous Vehicles
`Water
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`Natural water contains large number of dissolved and suspended
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`impurities. The dissolved impurities include inorganic impurities like
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`salts of sodium, potassium, calcium, magnesium and iron as chlorides,
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`sulfates and bicarbonates. Organic impurities present in purified water
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`are either in soluble or insoluble state. Micro-organisms are the other
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`impurities
`the load of micro—organism in natural substances-including
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`Water is called as bio—burden. Drinking water, termed as potable water
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`' in many texts, contains less than 0.1% of total solid‘ and in United States;
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`they should meet the requirements of U.S. Public health services
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`Vehicles — in pharmaceutical
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`formulations. are the liquid
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`bases that carry drugs and
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`other excipients in dissolved
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`or dispersed state.
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`Water — is the best vehicle
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`for liquid dosage forms but
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`Organic impurities present in
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`purified water either in
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`soluble or insoluble state
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`and Micro-organisms need_
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`purification by distillation, ion
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`exchange treatment or
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`reverse osmosis.
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`Page 7 of 59
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`

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`PI-lAl2MAcEUT[CAL-TECHNOLOGY
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`regulations with respect to bacteriologic purity (Bio-burden). In general,
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`acceptable drinking water should be clear, odourless, colourless and
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`neutral with slight deviation in pH (due to dissolved solids and gasses).
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`However, drinking water is not usable in pharmaceutical formulation,
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`obviously due to the possible incompatibility of formulation components
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`with dissolved impurities in water.
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`Purified Water USP is allowed for usage as vehicle or as a component
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`of vehicle for aqueous liquid formulations except for those intended for
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`parenteral administration (injections). It is obtained by distillation, ion
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`exchange treatment, reverse osmosis or any other suitable process from
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`Water complying with the Federal Environmental Protection Agency with
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`respect to drinking water. USP criteria for purified water (PW) compared
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`with USP Water for Injection (WFI) as condensed and / or excerpted from
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`section 643 and 645 of United States Pharmacopoeia (USP), 25th edition
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`is presented in Table 1.1.
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`-
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`Table 1.1. USP Purified Water (PW) and Water For Injection (WFI) Criteria
`Selected Criteria
`’
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`I
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`Parameter‘
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`pH
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`-
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`—
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`TOC (Total organic -
`carbon)
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`Total bacteria count
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`Endotoxin
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`PW
`5.0-7.0
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`< 500 ppb
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`10 colony forming units (cfu)
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`/InL, pathogen free
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`Not specified
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`10 colonyiorining units (cfu) / 100 mL,
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`pathogen free
`0.25 EU/ 1'nL
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`Conductivityillesistivity: USP defines the quality of water in terms of
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`conductivity. Conductivity criteria for PW and WI-‘I are the same. It is
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`measured in three stages. If the Stage 1 Criteria are not met, a Stage 2
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`should be conducted, and then if necessary (Stage 2 failure) a Stage 3
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`test may be conducted. The conductivity criteria measured in-line,
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`uncompensated for temperature, is listed in Table 1.2 and are referred to
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`as Stage 1 Criteria.
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`
`Conductivity I
`
`
`(Siam)
`0.6
`
`
`0.3
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`Table 1.2. Stage 1 Criteria
`- Resistivity
`Teniperature
`
`
`
`(M,--cm)
`("C3
`1.67
`45
`
`
`50
`
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`
`1.25
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`Conductivity
`
`
`(Siam) ‘
`1.8
`
`
`h
`
`1.9
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`Resistivity
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`Page 8 of 59
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`LIQUID DOSAGE FORMS
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`Alcohol (Ethyl Alcohol)
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`Next to water, alcohol is the most useful solvent in pharmacy. It is
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`invariably used as hydro-alcoholic mixture that dissolves both water
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`soluble and alcohol soluble drugs and excipients. Diluted alcohol NF,
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`prepared by mixing equal volumes of Alcohol USP and purified water
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`USP is a useful solvent in various pharmaceutical processes and
`formulations.
`
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`Next to water, alcohol is the
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`
`most useful solvent that is
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`invariably used as hydro-
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`alcoholic mixture
`that
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`dissolves both water soluble
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`and alcohol soluble drugs
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`and excipients.
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`Glycerin — is used as vehicle
`
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`.in various pharmaceutical
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`products like Elixirs.
`In
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`addition its use as a co-
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`It has acceptable
`solvent,
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`
`and
`taste
`increased
`
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`viscosity of the base.
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`Propylene Glycol is another
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`
`
`important ingredient due to
`
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`
`its activity as solvent,
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`
`
`wetting agent, emulsifier and
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`humectant.
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`Glycerol
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`Glycerol (or Glycerin) is a clear, colorless liquid, with thick, syrupy
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`consistence, oily to the touch, odourless, Very sweet and slightly warm
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`to the taste. When exposed to the air, it slowly abstracts moisture. Glycerol "
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`is obtained by the decomposition of vegetable or animal fats or fixed oils
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`and containing not less than 95 percent of absolute Glycerin. It is soluble
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`in all proportions, in Water or Alcohol; also soluble in a mixture of 3
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`parts of Alcohol and 1 part of Ether, but insoluble in Ether, Chloroform,
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`Carbon Disulphide, Benzin, Benzol, and fixed or Volatile oils. Glycerin
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`is used as vehicle in various pharmaceutical products like Elixir of
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`Phosphoric acid, Solution of Ferric Ammonium Acetate, Mucilage of
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`Tragacanthae, Glycerin of boric acid,‘ Glycerin of tannic acid, and in
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`many Extracts, Fluid Extracts, Syrups and Tincture/s.
`’
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`As glycerin is an excellent solvent for numerous substances, such as
`
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`iodine, bromine, alkalies, tannic acid, many neutral salts, alkaloids, salicin,
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`etc., it is a good Vehicle for applying these substances to the skin and to
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`sores. It does not evaporate not turn rancid, and is powerfully
`
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`hygroscopic. As glycerin is sweet, it is an excellent flavouring agent. It
`
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`is demulcent, and is used as a vehicle for applying substances, such as
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`tannic acid, to the throat. It is rarely given by the mouth for any medicinal
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`virtue. It hasvbeen administered for dyspepsia, for diabetes, and as a
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`nutritive agent, but in each case without any good result.
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`In oral liquid formulations, glycerin is used as co-solvent to increase
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`solubility of drugs that show low solubility in water. It is also used to
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`improve viscosity, taste and flavor. In external applications it is used as
`humectants.
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`Propyene Glycol USP
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`Pharmaceutical grade of Propylene Glycol is monopropylene glycol (PG
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`or MPG) with a specified purity greater than 99.8%. PG is an important
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`ingredient for a multitude of uses, including:
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`Page 9 of 59
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`

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`"
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`_ fiaamacsuricat 'r_£_c:.i-Is_oLoG'u'r
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`is also a
`Propylene glycol
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`
`
`It also has
`good cosolvent.
`
`
`
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`wetting,
`emulsifying,
`
`humactent and preservative
`
`
`P”3'P9'tY-
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`'
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`.
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`Solvent for aromatics in the flavour-concentrate industry
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`Wetting agent for natural gums
`
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`
`Ingredient in the compounding of citrus and other emulsified
`flavors
`
`Solvent in elixirs and pharmaceutical preparations
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`Solvent and coupling agent in the formulation lotion, shampoos,
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`creams and other similar products
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`
`
`a Emulsifier in cosmetic and pharmaceutical creams
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`0 Very effective humectants, preservative and stabilizer
`_ Propylene "glycol is an outstanding solvent for many organic
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`compounds. It is colourless and odourless and has a very slight
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`characteristic taste which is not objectionable. These properties make
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`propylene glycol particularly suitable as a solvent for flavourings and
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`dyes in cosmetics, toothpastes, shampoos, and mouthwashes.Propy1ene
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`glycol is non—allergenic and may be used in cosmetics and other toilet
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`goods specifically formulated for sensitive skin.
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`Propylene glycol is a general solvent and antimicrobial preservative
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`used in a wide range of pharmaceutical preparations including oral liquid,
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`topical and parenteral preparations. The toxicity of propylene glycol is
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`quite less in comparison to many other cosolvents generally used. As
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`per the Registry of toxic effects of chemical substances published by U.S.
`
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`Department of Health and Human Servi:ces{1986), the LD 50 of propylene
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`l<g"1, 8 g. kg’1 and 9.7 g. kg'1 when administered by oral,
`glycol is 24
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`IV and _IP respectively to mouse. However, In addition to risks associated
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`with adulteration, its use in large volumes in children is discouraged,
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`and it has been associated with CNS adverse events, especially in
`neonates.-
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`Lipid based deifvery —'
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`vehicles are suited for liquid.
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`formulation of low water
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`soluble drugs coming under
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`class II or [V drugs.
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`Lipid-Based Delivery Vehicles‘
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`A large number of new drugs being developed show low water solubility
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`and are characterized as either Class II or IV according to the
`biopharmaceutical classification system. To overcome low solubility and -
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`low bioavailability there has been a growing interest in developing novel
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`oral delivery strategies using lipid-based formulations. While oral liquid ,
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`emulsions have been used for many years, self-emulsifying drug delivery -'
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`systems, which utilize a lipid/surfactant-based vehicle, are becoming a
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`more widely used approach to solubilize water-insoluble drugs. Benefits
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`of these types of formulations are that lipids that keep a hydrophobic
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`drug in solution may facilitate the dissolution and absorption of the
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`drug as the lipid vehicle is -metabolized in the GI tract. The erratic
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`bioavailability of some drugs may be. overcome by formulation into a
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`Page 10 of 59
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`

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`LIQUID DOSAGE FORMS
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`microemulsion, which includes oil. A detailed discussion of such
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`formulations are dealt elsewhere in this chapter.
`
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`
`2.2 Solubilizers
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`
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`2.2.1 Wetting Agents and Surfactants
`
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`Wetting agents - are used
`
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`
`in liquid dosage forms to
`
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`
`
`a
`create
`homogenous
`
`
`
`dispersion of solid particles
`
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`in a liquid vehicle. Wetting
`
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`
`
`agents are Surfactants (HLB
`
`
`
`
`Value 7 to 9) that when
`
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`
`
`dissolved in water, lower the
`
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`
`
`Contact angle and aid in
`
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`
`
`spreadability of water on the
`
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`particles surface to displace
`
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`
`the air layer at the surface
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`and help in wetting and
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`
`
`solubilization.
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`Wetting agents are routinely used in pharmaceutical formulations,
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`especially in liquid dosage forms to create a homogeneous dispersion of
`
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`solid particles in a liquid vehicle. This process can be challenging due to
`
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`a layer of adsorbed air on the particle's surface. Hence, even particles
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`with a high density may float on the surface of the liquid until the air
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`phase is displaced completely. The use of a Wetting agent allows removal
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`of adsorbed air and easy penetration of the liquid vehicle into pores of
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`the particle in a short period of time. For an aqueous vehicle, alcohol,
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`glycerin, and PG are frequently used to facilitate the removal of adsorbed
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`air from the surface of particles. Whereas for a non-aqueous liquid vehicle,
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`mineral oil is commonly used as a Wetting agent.
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`Typically, hydrophobic API particles are not easily wetted even after
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`the removal of adsorbed air. Hence, it is necessary to reduce the interfacial
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`tension between the particles and the liquid vehicle by using a surface-
`
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`
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`active agent. Structurally, Wetting. agents comprise branched hydrophobic
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`chains with central hydrophilic groups or short hydrophobic chains with
`
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`hydrophilic end groups. For example, sodium lauryl sulfate is one of the
`
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`
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`most commonly used surface—actiVe agents. Such surfactants, when
`
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`
`
`dissolved in Water, lower the contact angle of Water and aid in
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`spreadability of water on the particles surface to displace the air layer
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`at the surface and replace it with the liquid phase. Wetting agents have
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`a hydrophilic—lipophilic balance (HLB) Value between 7 and 9.
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`The following properties must be considered in the assessment of
`
`
`Wetting agents:
`0 The minirnum surface tension that can be attained, regardless of
`
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`
`
`'
`the amount of agent required.
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`e The depression of surface tension achieved With a specified
`
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`concentration of agent.
`'
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`c The time required for an agent to achieve equilibrium. A good
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`wetting agent permits the depression of surface tension in water
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`by up to 2.5 mN/m in 15 seconds.
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`Careful consideration must be given to the potential changes in
`
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`activity and bioavailability of the API and/or excipients when a surfactant
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`is used. Dramatic changes in the bactericidal activity of certain excipients
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`take place when they are solubilized by surfactants, and the stability of
`excipients against oxidation and hydrolysis may be modified by .l
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`solubilizatiofi. Additionally, many nonionic surfactants (at high
`
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`Wetting agents — are
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`
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`surfactents like tweens,
`
`
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`spans, poloxamers etc.,
`
`
`
`which reduce the interfacial
`
`
`
`
`tension
`between
`the
`
`
`
`particles and the liquid
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`and
`vehicle
`promotes
`
`
`
`wetting and solubilization.
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`Page 11 of 59
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`

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`I PHI-\l?MACEUTlt"JAL TECHNOLOGY
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`concentrations) exhibit a characteristic temperature above which the
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`solution becomes cloudy. This cloudiness is due to the formation of very
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`large lamellar micelles, which results from the dehydration of the
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`polyoxyethylene chains. For these types of surfactants, it is essential to
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`‘consider the risk of exceeding the cloud point.
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`The physicochemical characteristics of some typical wetting agents
`
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`
`
`and/or solubilizing agents are listed in Table 1.3.
`
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`
`
`Table 1.3. Physicochemical Characteristics of Wetting/Solubilizing Agents
`
`
`
`.
`
`Wettinglsolubilizing Agents
`
`
`
`
`=
`
`1
`
`Solubility
`
`
`
`Benzalkonium chloride, NF
`
`
`Benzethonium chloride
`
`
`
`
`
`‘
`
`'
`
`
`
`
`
`Cetylpyridinium chloride, USP
`» Docusate sodium, USP
`
`
`
`
`
`Nonoxynol 9 USP
`Octoxynol
`I
`
`Polpx-amer NF ‘
`
`
`Poloxamer 124NF
`
`
`Poloxamer 188, 237, 338, 407 NF
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`Polyoxyl 35 castor oil NF
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`Polyoxyl 40 hydrogenated
`Castor oil NF
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`Polyoxyllo oleyl ether, NF
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`. Polyoxyl 20 cetylstearyl ether, NF
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`Polyoxyl 40 stearate, NF
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`Polysorbate 20 NF
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`Polysorbate 40 NF
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`Polysorbate 60 NF _
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`Polysorbate 80 NF
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`Sodium lauryl sulfate, NF
`Sorbitan monolaurate‘ NF
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`= Sorbitan monooleate NF
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`.Sorbitan monopa1mitate.NF
`Sorbitan monostearate NF
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`»
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`4
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`A
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`.
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`Tylcixapol USP
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`V
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`‘
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`Abbreviations of Solubility: VS, very soluble, FS, freely soluble, SOL,
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`soluble, SPSOL, SLSOL, VSS, Very slightly soluble, INSOL, practically
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`insoluble or insoluble, MISC, miscible.
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`Page 12 of 59
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`Liouio name Foams
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`In addition to the concentration of surfactant, the location of the API
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`or excipient in the micelle structure can influence its stability. Surrounding
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`the positive surface of the cationic rnicelle will be a relatively higher
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`concentration of hydroxyl ions from the surrounding solution. If the
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`drug or excipient is more susceptible to base—catalyzed hydrolysis and
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`exposed to the concentrated hydroxyl area near the surface of the micelle,
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`then the result would likely be more degradation (hydrolysis). However,
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`if it is more stable under alkaline conditions, then there may be less
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`degradation (hydrolysis). Therefore, if a correlation between the location
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`of the drug or excipient in the micelle and its pl-I—dependent stability can
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`be determined, a formulator may be able to optimize the choice of
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`surfactant to prevent degradation.
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`2.2.2 pH Modifiers and Buffering Agents
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`The pH of an oral liquid formulation is a key point in many regards.
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`Control of the formulation pH, could prevent large changes during
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`storage. Therefore, most formulations utilize a buffer to control potential
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`changes in the solution pH. The amount of buffer capacity needed is
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`generally between 0.01 and 0.1 M, and a concentration between 0.05 and
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`0.5 M is usually sufficient. The selection of a suitable buffer should be
`based on
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`(1') Whether the acid.-base forms are listed for use in oral liquids,
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`(ii) The stability of the drug and excipients in the buffer, and
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`(iii) The compatibility between the buffer and , container. A
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`combination of buffers can also be used to gain a wider range of
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`pH compared to the individual buffer alone. However, not all
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`buffers are suitable for use in oral liquids. For example, a boric
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`acid buffer may be used for optical and IV delivery but not in
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`oral liquids‘ because of its toxicity.
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`Stability of formulation containing non-ionizable API may also
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`depends on pH. For example, a specific functional group or a particular
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`resonance structure that is stabilized in a specific pH range may facilitate
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`a reaction between the excipient and the drug.
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`However, the buffer may negatively influences the solubility of the
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`drug and other excipients. The effect depends on a combination of the
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`polarity of the solute and of the salt. Non-polar solutes are solubilized
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`(salted in) by less polar organic salts and are desolubilized (salted out)
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`by polar salts. Conversely, polar solutes are salted in by polar salts and
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`salted out by organic salts.
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`The stabilizing effect of buffers that have multiple. charged species
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`in solution could also determine the potential reaction between excipients
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`and API. For example, buffers that use carbonates, citrate, tartrate, and
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`Various phosphate salts may precipitate with calciumions by forming
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`sparingly soluble salts. However, this precipitation is dependent upon
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`the solution pH. The activity of phosphate ions may be lowered due to
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`interactions with other solution components.
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`There are a number of factors that may also affect the solution pH
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`such as temperature, ionic strength, dilution, and the amount and type _
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`liquid
`The pH — of an oral
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`formulation is a key point for
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`API stability, solubilization
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`also
`and
`to prevent
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`microbial contamination.
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`_ Buffers are used to control
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`pH _ of
`liquid
`orals.
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`Combination of bufiers can
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`_also be used to gain a wider
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`range of pH compared to the
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`individual buffer alone.
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`Buffer selection should be
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`judicious
`to
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