Il Farmaco 54 (1999) 1–14
`
`Review
`Quality and functionality of excipients
`
`Giorgio Pifferi a,*, Paola Santoro a, Massimo Pedrani b
`a Istituto di Chimica Farmaceutica e Tossicologica, V.le Abruzzi 42, I-20132 Milan, Italy
`b Emmiepi-Pharma, V.le Arbe 77, I-20125 Milan, Italy
`
`Accepted 15 September 1998
`
`Abstract
`
`The quality of medicines depends not only on the active principles and production processes, but also the performance of the
`excipients. The traditional concept of the excipient as any component other than the active substance has undergone a substantial
`evolution from an ‘inert’ and cheap vehicle to an essential constituent of the formulation. The rapid evolution of scientific,
`regulatory and economic factors, the introduction of delivery systems and the advance in biopharmaceutics have led to a new
`interest in the role and functionality of the excipients. More than one thousand raw materials are available from a multitude of
`sources and are used today in the pharmaceutical industry. Their chemical structures vary from small molecules to complex
`natural or synthetic polymeric mixtures. Excipients are now chosen to perform a variety of functions to guarantee the stability and
`bioavailability of the drug substance from the drug product and its manufacturability on a production scale. Beyond the dosage
`form necessities, excipients are required to perform important and specific technological functions, particularly in the case of solid
`dosage forms. As a consequence, their characterisation must go beyond the simple tests for identity, purity and strength as
`prescribed in general by the Pharmacopoeia monographs. With the exception of the Textbook of Pharmaceutical Excipients, not
`many reference sources describing the physical mechanical characteristics of the powders for a specific role are available. Full
`physical characterisation of solid materials is now made possible with the help of high resolution analytical techniques on the
`molecular, particulate and bulk levels. This systematic approach is necessary to guarantee the behaviour of the excipient during
`the formulation and production phases. Some examples have been chosen in this mini-review in an effort to highlight the emerging
`trends in the development of ‘tailor-made’ materials. Three main approaches are followed by the industry: physical or minor
`chemical manipulation of materials already known, combination of two or more marketed excipients in order to reduce unwanted
`defects and, finally, preparation of new chemical entities with huge investments for the toxicity studies. Excipient harmonisation,
`standardised functionality tests, preformulation data bases and expert systems will contribute to change the conventional
`trial-and-error formulation approach into a far more scientific and technological development. © 1999 Elsevier Science S.A. All
`rights reserved.
`
`Keywords: Excipient performance; Pharmacopoeial standards; Solid material characterisation; Pregelatinised starch; Microcrystalline cellulose;
`Amorphous lactose
`
`1. Evolution of the concept of the excipient
`
`1.1. Traditional concept of the excipient
`
`The biological and analytical requirements necessary
`for the registration of an active principle as a medicinal
`speciality, whether of natural or synthetic origin, have
`
`* Corresponding author.
`
`always been at the centre of the pharmaceutical indus-
`try’s and health authorities’ attention [1]. Ever increas-
`ing demands and expectations with regard to quality
`have stimulated the development of new drugs charac-
`terised by higher assay and lower content of impurities
`[2]. However, the quality of a drug does not depend
`only on the characteristics of the active substances and
`the production process but also partly on the quality of
`the excipients. In general, the latter contributes notably
`
`0014-827X:99:$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
`PII: S 0 0 1 4 - 8 2 7 X ( 9 8 ) 0 0 1 0 1 - 3
`
`Opiant Exhibit 2303
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 1
`
`

`

`2 t
`
`o the performance of the drug and this, contrary to
`what was believed in the past, is fundamental to guar-
`antee the safety and efficacy of the final pharmaceutical
`product [3]. Confirmation of this ‘historical’ under-esti-
`mation of the role played by the excipient is already
`discernible in the definition of the traditional concept
`which saw it simply as a substance that facilitates the
`administration and preservation of the active principle.
`Some factors outside the pharmaceutical sector, such
`as the supply sources, the quality of the material, the
`manufacture and marketing of raw materials (Table 1)
`justify, at least in part, the scant attention paid to the
`matter of excipients up to a few years ago. This attitude
`was also engendered by the very low incidence of the
`cost of the excipients in the global cost of the com-
`pound, often lower than 1%. On the other hand, if we
`take into consideration the composition of a medicinal
`product from the point of view of its weight, it will be
`noted that the percentage of the active principle con-
`tained in the formula is generally considerably lower
`than that of the excipients. In the three drugs shown as
`examples in Table 2, the weight of the active principle
`varies from a maximum value of 12% in the formula-
`tion of sugar-coated tablets, to 0.5% in drops, to the
`
`G. Pifferi et al. :Il Farmaco 54 (1999) 1–14
`
`lowest content of 0.0008% in the preparations for am-
`poules. These percentages become simply infinitesimal
`if homeopathic preparations are taken into consider-
`ation, seeing that they are obtained from successive
`dilutions of thousandths from the parent tinctures [4].
`From the chemical point of view, even the so-called
`inertia of the excipients is to be accepted with reserva-
`tions. In fact, like active principles, excipients have their
`own internal thermodynamic energy. This results in a
`certain reactivity which, though low, may, when influ-
`enced by chemical and physical factors in the environ-
`ment, trigger some reactions leading to degradation,
`with fortunately usually slow kinetics. In the formula-
`tions in Table 2 there are some excipients containing
`reactive organic functions such as ethyl alcohol and
`propylene glycol, the terpenic essences in flavourings,
`iodised colourings,
`iron oxides and complexing (ex.
`EDTA) and reducing substances such as lactose. Con-
`siderable percentages of chiral excipients (starch, cellu-
`lose) are also employed and these may react with
`racemic active principles due to the law of mass, giving
`rise to diastereoisomers endowed with different chemi-
`cal properties and therefore different bioavailability [5].
`Another fundamental characteristic of the classical
`excipient, besides its so-called chemical inertia, is its
`pharmacological and toxicological inacti6ity. One cannot
`generalise in this case either when one thinks of the use
`that has been made of ethanol and boric acid, sulfites
`and tartrazine with their immunological effects, organic
`mercury compounds and some mineral oils, not to
`mention the psychological effects of excipients as
`placebos.
`From these preliminary remarks it is clear that the
`two traditional requirements of an excipient, inertia and
`pharmacological and toxicological
`inactivity, are not
`always met. The supposed inertia of an excipient is
`often more of an expectation than the result of a real
`thermodynamic paralysis. Only a thorough study in the
`
`Table 1
`The traditional excipient
`
`Source
`
`Production
`
`Quality
`
`Market
`
`From a multitude of natural sources, in general as
`a complex mixture of similar compounds, and from
`synthetic polymers.
`For chemical, food, agricultural and cosmetic in-
`dustries, partly and not particularly, for the phar-
`maceutics industry.
`Often not suitable for pharmaceutical use, tested
`by the consumer, not by the manufacturer, physical
`properties not qualified as excipient.
`Raw materials for commercial scale productions,
`with limited grade offered, low price and no trade-
`mark.
`
`Table 2
`Weight ratio between active principle and excipients
`
`Valium®2 guttae
`
`Diazepam
`
`Colourant E 127
`Alcohol
`Propyl glycol
`Saccharin
`Orange ess.
`Lemon ess.
`Colourant E 127
`Water
`
`Ratio(cid:30)0.5%
`
`mg 5
`
`to ml 1
`100
`600
`11.4
`20
`10
`9.2
`to ml 1
`
`Laroxyl® pills
`
`Turbocalcin® vials
`
`Amitriptyline
`
`mg 11
`
`Carbocalcitonin
`
`Colourant E 172
`Starch
`Lactose
`PVP
`Magnesium stearate
`Gum arabic
`Ethyl cellulose
`Colorant E 172
`Titanium oxide
`Paraffin
`Sucrose
`Ratio(cid:30)12%
`
`mcg 500
`10.6
`17.5
`0.9
`4.1
`1.1
`0.3
`mcg 25
`mcg 500
`14
`to 90
`
`Turbocalcin1vials
`Sodium chloride
`Sodium acetate
`Acetic acid
`W.F.I
`
`Ratio(cid:30)0.0008%
`
`mg 8
`
`to ml 1
`mg 7.5
`2
`
`to ml 1
`
`Opiant Exhibit 2303
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 2
`
`

`

`G. Pifferi et al. :Il Farmaco 54 (1999) 1–14
`
`3
`
`preformulation phase will show which are the most
`suitable excipients, clarify their reciprocal interactions
`and evaluate their real contribution to the efficacy of
`the medicinal product [6].
`
`1.2. The excipient as adju6ant agent
`
`The majority of pharmaceutical dosage forms falls
`into the category of solid, semi-solid and liquid disperse
`systems, in which the active principle:s are considerably
`diluted, as we have seen. The excipients have therefore
`to carry out the functions of diluent, filler and solvent
`so as to give the dose of active principle suitable weight,
`consistency and 6olume from the galenic point of view,
`and make it more convenient to administer [7]. In this
`case, the excipient assumes the function of 6ehicle suit-
`able for the desired administration route, so as to
`transport the active principle to the desired place of
`absorption in the organism. The study and creation of
`more or less complex disperse systems require a suffi-
`cient knowledge of physical chemistry and physics to be
`able to assess their contribution to the stability and
`release of the active principle.
`Besides the traditional functions of support and vehi-
`cle therefore, the excipient is also expected to function
`as an adju6ant, from the Latin verb ‘adju6are’, that is to
`help the active principle to carry out its activity by
`conditioning its release from the pharmaceutical dosage
`form. In the National Formulary Admission Policy of
`1994 [8] there is the following definition: ‘‘Excipients
`are any component other than the active substance(s)
`intentionally added to the formulation of a dosage
`form.’’ To interpret the adverb ‘intentionally’ in this
`definition, we must remember the main administration
`routes of a medicinal product and the complexity of the
`roles the excipient must play in their respective formu-
`lations [9]. For each of the administration routes indi-
`cated in Table 3, the excipient must guarantee the
`stability of the pharmaceutical dosage form, the preci-
`sion and accuracy of the dosage, as well as modify,
`when necessary, its organoleptic characteristics (smell,
`taste, swallowability and local tolerability) so as to
`improve the patient’s ‘compliance’.
`
`Table 3
`The excipient in modern formulations
`
`Routes of administration
`
`Roˆles to enhance
`
`Oral
`Rectal and vaginal
`Inhalation
`Topical
`Transdermal
`Intraocular
`Intranasal
`Parenteral
`
`Organoleptic properties
`Compliance
`Dose precision and accuracy
`Stability
`Side-effects
`Desaggregation, dissolution
`Controlled release
`Absorption
`
`To these traditional roˆles are added today those of
`controlling and regulating the rate of disaggregation
`and dissolution, with possible favourable repercussions
`on the release profile of the active principle and its
`bioavailability, understood as the speed and amount of
`active principle
`released from the pharmaceutical
`dosage form and entering the systemic circulation. The
`pharmaceutical dosage form thus outlined can optimise
`the therapeutic efficacy of the medicinal product while
`simultaneously reducing its undesired side effects. The
`study of the formulation of a medicinal product on an
`empirical basis is now a thing of the past and Pharma-
`ceutical Technique is gradually and inevitably changing
`from an Art (witness the italian initials FSA: fai sec-
`ondo arte) into an Applied Science, which requires
`multi-disciplinary competence, as we shall see further
`on.
`
`1.3. The e6olution of excipients
`
`From the standpoint of what we have said so far, the
`excipient is no longer to be considered an inert product
`but an essential and functional component of a modern
`pharmaceutical dosage form [10]. What are the external
`factors that have contributed to this evolution, not only
`in the concept but also in the regulations governing
`excipients? In Table 4 certain elements have been sum-
`marised so as to facilitate the understanding of the
`rapid and profound change in the characteristics and
`quality of excipients which has occurred since the 1970s
`and 1980s [11].
`The globalisation of demand and economies of scale
`are the consequences of an industrial philosophy that
`rewards partnerships and mergers between pharmaceu-
`tical companies with the formation of important multi-
`national companies enjoying considerable financial
`reserves. This enables them to support the basic and
`applied research activities necessary to innovate their
`range of products in the future. The organisation of
`work ( just in time), too, and the size and scattered
`locations of the production plants are rapidly undergo-
`ing transformation and rationalisation so as to reduce
`as much as possible the time required for development
`and the number and variability of production batches.
`As a reflection of this, even the machinery, such as
`ampoule-fillers, tabletting and encapsulating machines,
`has to be re-designed so as to work at high speeds.
`It follows that it is necessary to have at one’s disposal
`new excipients that are compatible not only with mod-
`ern processes and production machinery (rotating and
`not conventional tabletting machines, rotating granula-
`tors, compactors, etc.) but also with inno6ati6e acti6e
`principles coming, that is, from biotechnologies and
`modern peptide synthesis [12]. Moreover, the interest in
`and wide-spread use of new therapeutic systems and
`modified-release forms is another factor that spurs the
`demand for more sophisticated excipients that can fulfil
`
`Opiant Exhibit 2303
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 3
`
`

`

`G. Pifferi et al. :Il Farmaco 54 (1999) 1–14
`
`4 T
`
`able 4
`Factors impacting on the evolution of excipients
`
`Scientific and regulatory factors
`National Formulary as exclusive
`Excipient Compendium
`Over 100 new monographs
`added to NF
`NF Panel on Moisture
`Characterisation
`USP:NF Special Advisory Panel
`in Physical Test Methods
`Int. Pharmac. Excipient Council
`(IPEC) Foundation
`Int. Pharmac. Excipient Council
`European Conference
`Eur. Pharmacopoeia Group of
`Experts to Test Functionality
`The Int. Conference on
`Harmonisation
`Handbook of Pharmaceutical
`Excipients
`
`Technological and economic factors
`Higher productive power
`
`New excipients
`
`Globalisation demand
`
`(1980)
`
`(1975–1990)
`
`(1985–1990)
`
`(1991)
`
`(1991–1994–1998)
`
`(1994)
`
`(1995)
`
`ICH (1991), ICH 2 (1993),
`ICH 3 (1995), ICH 4 (1997)
`I ed. (1986)
`II ed. (1995)
`
`(tablet presses with higher
`compaction speeds, non
`conventional rotary presses,…)
`(for novel and potent drugs,
`for biotechnology products, for
`controlled release formulations,
`for new delivery systems,…)
`(organisational restructuring,
`merging, just-in-time,
`automation,…)
`
`specific functions within the formulation. These inno-
`vative formulations permit the optimisation of plas-
`matic concentrations of
`the active principle,
`thus
`increasing efficacy, the patient’s compliance and the
`added value of the medicinal product [13].
`The scientific and regulatory events that have con-
`tributed to the evolution of the excipients sector over
`the last twenty years, in concomitance with the eco-
`nomic and technological factors, are not to be ne-
`glected. Returning to the
`situation in the past,
`excipients were taken from materials of natural origin
`and in common use in the chemical and agricultural
`food-stuffs sectors and employed in the pharmaceuti-
`cal field just as they were, without further purification
`to improve the assay or their chemical or physical
`characteristics. Analytical tests were conducted for the
`most part within the Pharmaceutical Industry and not
`by the supplier of the raw material. The tests were
`often limited and not sufficient
`to characterise the
`excipients’ quality, much less their functionality. To
`give a few examples, only one type of ‘spray-dried’
`lactose was available for the production of tablets
`and capsules by direct
`compression. Magnesium
`
`stearate was widely employed as a lubricant, even
`though there was scant knowledge of its structure and
`lubricating capacity. Since 1970,
`the situation has
`evolved swiftly under the pressure of new knowledge
`of
`the solid state of materials and the ever more
`stringent qualitative requirements demanded by the
`Regulatory Authorities.
`Table 4 lists some scientific events, such as the in-
`clusion of over a hundred monographs on excipients
`in the US National Formulary and the publication of
`two editions of the ‘Handbook of Pharmaceutical Ex-
`cipients’, which contains monographs that meet phar-
`maceutical
`technologists’ needs much more closely
`[14]. Furthermore, at the beginning of 1990, the Sec-
`retaries of the three most important Pharmacopoeias,
`the USP, the Eur. Ph. and the J. Ph., agreed on the
`importance of harmonising the standards and the
`testing methods regarding excipients, so as to satisfy
`the requirements of the industry and their own re-
`spective Regulatory Agencies. Considerable progress
`has been achieved since 1990 (Table 4) as a conse-
`quence of a good four Joint Pharmacopoeial Open
`Conferences on International Harmonisation of Ex-
`cipient Standards and four ICH (Brussels, November
`1991; Orlando, October 1993; Yokohama, November
`1995; Brussels, 1997). The monograph on lactose
`monohydrate has reached the last stage of publication
`and
`those
`on magnesium stearate,
`saccharose,
`polyvinylpirrolidone as well as powdered and micro-
`crystallised cellulose are at advanced stages in the
`procedure [15,16]. Some testing methods on the physi-
`cal state, such as particle size, specific superficial area,
`poured and tapped density are also in an advanced
`phase of joint compilation.
`The renewed interest in modified release forms and
`in new therapeutic systems, as well as new production
`technologies, has contributed, as already mentioned,
`to research into new materials endowed with specific
`technological properties and their development as
`functional excipients. All these factors and more have
`changed the traditional concept of an excipient into
`the more up-to-date one of functional agent, that is,
`one that can fulfil several functions within the phar-
`maceutical formulation. They have also contributed
`to focusing the pharmaceutical technologists’ attention
`on the quality of the excipient, which also contributes
`to the efficacy and safety of use of the medicinal
`product, together with that of the active principles.
`
`2. Functions and specifications of excipients
`
`2.1. Functions of excipients
`
`On the basis of the preceding considerations, it is
`clear that excipients are no longer to be considered as
`
`Opiant Exhibit 2303
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 4
`
`

`

`G. Pifferi et al. :Il Farmaco 54 (1999) 1–14
`
`5
`
`Table 5
`Modern excipient functions
`
`Stability
`
`Drug absorption
`
`Antioxidants
`Chelating agents
`Preservatives
`Stabilisers
`Buffers
`pH modifiers
`
`Manufacturability
`
`Disintegrants
`Plasticisers
`Drug release modifiers
`Penetration enhancers
`Wetting agents, solvents
`Film formers
`Bioadhesives
`Encapsulating agents
`Biodegradable polymers
`
`Dosage form necessities
`
`Specific techn. Properties
`
`Ointment bases
`Semisolid excipients
`Diluents,…
`
`Emulsifying, suspending ag.
`Gelling agents
`Lubrication enhancers
`Flow, compaction enhancers
`Propellents, bulking agents,…
`
`inert materials but essential components of ever more
`sophisticated and modern pharmaceutical dosage forms.
`Excipients are employed to carry out different functions
`that may be grouped into three categories, according to
`whether they influence stability, release and absorption
`of the active principle or manufacturability during the
`manufacturing process phase [17]. Excipients with this
`latter function may be subdivided in turn into those that
`are basic components of a certain pharmaceutical
`dosage form (dosage-form necessities), such as ointment
`bases, or into a second sub-group of materials that can
`fulfil particular technological functions, such as lubri-
`cants (Table 5). Thus, by varying the type, quantity and
`quality of the excipient incorporated, the pharmaceuti-
`cal technologist can correct and optimise the character-
`istics of the final formulated product.
`In the case of the manufacture of tablets and hard
`capsules, for instance, modern excipients must be suit-
`able for the preparation of homogeneous and flowable
`mixtures during the intermediate manufacturing process
`
`Table 6
`Modern excipient specification
`
`of the powders and granulates, so that the modern
`tabletting and encapsulating machines are fed swiftly
`and smoothly. In order to fulfil the multiple functions
`shown in Table 5, the specifications of modern-day
`excipients must add a series of technological functional
`measures to the normal characterisation of analytical
`purity [18,19]. The technological tests of physical chem-
`istry and mechanical physics are drawn up schematically
`in Table 6 and are as important today as the traditional
`tests that were carried out to ascertain the analytical
`identification, assay and purity of the active principle.
`
`2.2. Pharmacopoeial monographs and their limitations
`
`Confirmation of the gaps in the analytical specifica-
`tions of excipients may be gathered from reading the
`on magnesium stearate
`monograph
`(magnesium
`stearicum) in the Italian Official Pharmacopoeia IX
`Edition [20], where the following tests are prescribed:
`(cid:147) Composition: mixture of variable and unspecified
`proportions of magnesium stearate, palmitate and
`oleate.
`(cid:147) Title: Mg between 3.8 and 5%.
`(cid:147) Organoleptic characters: very fine powder, white,
`oily…
`(cid:147) Solubility: practically insoluble in water, ethanol and
`ether.
`(cid:147) Identification: melting point of organic residue, char-
`acteristic reactions of magnesium.
`(cid:147) Assays: colorimetric comparison of solution S with a
`comparable solution, appearance of chloroform so-
`lution of fatty acids.
`(cid:147) Acidity or alkalinity: blue indicator of bromothymol.
`(cid:147) Acidity index of fatty acids: between 295 and 210.
`(cid:147) Chlorine, sulfate and heavy metals test: within the
`limits.
`(cid:147) Loss on drying: equal to or lower than 6% at 100–
`105°C.
`The quantitati6e determination prescribes the com-
`plexometric titration of magnesium with zinc sulfate
`and sodium edetate.
`
`The tests on the functionality of the excipients comprehend:
`
`Control of purity
`Chemical characterisation: identity, purity, strength, composition
`Control of performance
`Physico–mechanical testing:
`relates to a specific application (what the excipient does)
`
`Physical characterisation:
`describes the functional attributes that make the excipient perform
`(why the excipient does what it does)
`Excipient specifications thus ensure the dosage-form necessities:
`Safety, Stability, Absorption, Manufacturability
`
`Opiant Exhibit 2303
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 5
`
`

`

`6
`
`G. Pifferi et al. :Il Farmaco 54 (1999) 1–14
`
`The method employed to produce the raw material is
`not requested, the purity test employs dated analytical
`methods and totally absent are the testing of the physi-
`cal chemistry, physical and functional parameters,
`which characterise the mechanical physical performance
`of the lubricant.
`These shortcomings in the Pharmacopoeia’s mono-
`graphs (F.U.I. IX Ed., N.F., and others) are no longer
`acceptable because it has been demonstrated that chem-
`ically similar materials do not always give the same
`results during the manufacturing phase. For greater
`clarity, Table 7 lists some of the parameters of magne-
`sium stearate that it is important to know so as to assess
`its efficacy as a lubricant. It is to be noted that this
`excipient can be produced industrially in widely differ-
`ing crystalline forms and sizes by melting and milling or
`by precipitation in an aqueous suspension [21].
`The above-mentioned shortcomings are also repeated
`in other monographs on excipients in the F.U.I. IX Ed.
`as, for example, in those on lactose (lactosum), which
`do not go beyond the usual approximative description
`of the characteristics, the solubility in water and alcohol
`of its organic and inorganic impurities (proteins and Pb
`respectively) and instead emphasises the aspects con-
`cerning identification and assays (acidity, water content,
`specific rotation capacity and bacterial contaminants).
`But to which lactose do the monographs refer? There
`are several types of lactose on the market: monohy-
`drate, anhydrous, spray-dried; they are listed in Table 8
`together with the principal characteristics that modify
`the functionality of this excipient [15].
`These two examples of widely-used excipients confirm
`that verification against the traditional monographs is
`not sufficient, because the latter are based to too great
`an extent on simple identification tests and often out-
`dated chemical assays for purity, with no sort of testing
`of the functionality of the excipient itself. Furthermore,
`the up-dating of the monographs relating to the excipi-
`ents more recently used is not timely [22]. This type of
`
`Table 7
`Lubricant activity of magnesium stearate
`
`Manufacturing methods Melting of the starting materials
`Precipitation in an aqueous suspension
`of fatty acids and Mg salts
`Breaks the crystal structure
`Anhydrate, dihydrate,…
`Pure or mixtures
`Layered plates or flakes, 1.5–13 mm
`0.25–0.45 g:ml
`1–5–54 m2:g
`Lod: 50.5% at 80°C
`Dissolution decrease
`
`Milling
`Polymorphism
`Purity
`Particle size and shape
`Bulk density
`Specific surface area
`Moisture content
`Blending time
`
`Table 8
`Lactose functionality
`
`Single compound
`Optical activity
`Types
`
`Manufacturing methods
`Particle size distribution
`Specific surface area
`Density
`Loss on drying (lod)
`Water test
`
`Crystallinity degree
`Volatile impurities (ovi)
`
`Galactose–glucose disaccharide
`Dextrorotatory 54.4–55.9°
`a-Monohydrate, a-anhydrate,
`b-anhydrous
`Spray-drying, roller drying,…
`50–400 mm
`0.35–1.0 (m2:g)
`1.540 (a); 1.589 (b)
`0.1–0.5% at 80°C for 2 h
`1% for monohydrate and modified
`lactose
`Amorphous form may be present
`If organic solvents are used
`
`‘traditional’ specification is therefore not suitable to
`discriminate between batches of similar purity but with
`different characteristics in the solid state, such that can
`modify the processability and behaviour of the interme-
`diate and final formulation. The consequent problems
`concern the variability from one batch to another, the
`inadequate knowledge of the formation of the solid
`particles and their interactions. The traditional methods
`to test the physical properties also depend on the type
`of technique employed and often give results that can-
`not be compared from one laboratory to another. There
`are also no screening methods for materials that are
`sensitive to the conditions prevailing during the formu-
`lation process.
`
`3. Characterisation of excipients in the solid state
`
`3.1. Physical properties of excipients
`
`Given the numerous and complex functions that a
`modern excipient must fulfil, its characterisation must
`go well beyond the simple tests for identity, purity and
`titre as prescribed in the Pharmacopoeia monographs in
`general, and be extended to testing the technological
`functionality of the material, which is usually employed
`in the solid state. By functionality we mean the physical,
`physicomechanical and biopharmaceutical properties.
`This testing is complicated by the fact that excipients
`are not generally made up of single chemical entities but
`comprise more or less complex mixtures of polymers
`and synthetic and semi-synthetic natural derivatives
`designed for multiple uses in, for instance, food-stuffs,
`cosmetics and pharmaceuticals.
`Considering the clear prevalence of solid forms in the
`pharmaceutical armamentarium, particular attention
`ought therefore to be paid to the study of excipients in
`the solid state at various levels of complexity: molecule,
`particle and aggregate. In Table 9 the right-hand
`
`Opiant Exhibit 2303
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 6
`
`

`

`G. Pifferi et al. :Il Farmaco 54 (1999) 1–14
`
`7
`
`Table 9
`Characterisation of raw materials in solid form
`
`Scale of scrutinity
`
`Property grouping
`
`Properties studied
`
`Molecule
`
`Molecular
`Solid state
`Crystallographic
`
`Microcrystal
`
`Particle
`
`Particle assembly
`
`Bulk powder
`
`Particulate
`
`Derived bulk
`
`Structure
`Phase analysis
`Polymorph.:solvates
`Crystallinity
`Solubility
`Mechanical
`
`Particle size and shape
`Surface
`Dissolution
`
`Packing
`Flow
`Compaction
`
`column lists the properties that may be studied according
`to the increasing state of aggregation (crystal, particle or
`group of particles). The first column lists the analytical
`methods that can be used to examine the molecule, the
`microcrystal, the particle or the bulk powder as such,
`even though it must always be borne in mind that the
`properties of the single unit are obviously correlated with
`those of the aggregates [23]. The manufacturing methods
`(precipitation, crystallisation, nebulisation, freeze-dry-
`ing,…) and the process variables (temperature, stirring,
`saturation,…) have a considerable influence on these
`properties of the material.
`
`3.2. High-resolution analytical techniques
`
`The recent improvements in high-resolution analytical
`techniques and in the science of materials, allow for the
`
`determination of even small differences in batches of
`excipients and active principles, even if they are equiva-
`lent from the chemical point of view. The characterisa-
`tion of the solid state and the surface parameters [24] is
`therefore fundamental first to assess and then guarantee
`the behaviour of the excipient in the formulation and
`production phases. Of particular interest are infrared
`spectroscopy and nuclear magnetic resonance to deter-
`mine the molecular structure and possible chemical
`interactions (Fig. 1). Calorimetry and, above all, TGA
`and DSC analysis are often adopted to clarify stability,
`compatibility, degree of crystallinity and transitions of
`phase of the excipients. The structure of the single crystal
`or the powder can be examined with absolute certainty
`by X-ray diffraction. The hygroscopicity of powders and
`the possible formation of hydrates are revealed by
`isothermic absorption tests.
`Even though the theoretical basis necessary to predict
`the behaviour of solid excipients is not yet completely
`clarified, so that they could be designed to meet optimal
`requirements for a particular manufacturing procedure,
`it is possible, however, to plan a series of preliminary
`technological tests to supply useful information in the
`preformulation phase. For obvious reasons of economy,
`the tests selected and carried out will be only those that
`are indispensable for the formulator to overcome the
`difficulties encountered according to the type of formu-
`lation and the performance desired. Further, more so-
`phisticated tests to examine the matter more deeply will
`be carried out only if necessary. In the preformulation
`phase it is indispensable to activate a first level of enquiry,
`such as chemical and spectroscopy tests on structure,
`composition, purity and polymorphism at the molecular
`level. Routine technological tests will then follow on the
`
`Fig. 1. High-resolution analytical techniques used for pharmaceutical excipients.
`
`Opiant Exhibit 2303
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 7
`
`

`

`8
`
`G. Pifferi et al. :Il Farmaco 54 (1999) 1–14
`
`Fig. 2. Testing procedure for powdered raw materials.
`
`granulometrics, specific area, density and tapped density
`at the particle level [25,26]. The upper levels 2 and 3 of
`Fig. 2 will be activated only when more exact information
`is required on the rheological and mechanical physical
`behaviour of the powders and aggregates in the particu-
`lar manufacturing process and with a view to obtaining
`the optimal performance of the formulated product. A
`thorough understanding of the specific properties of a
`material can lead to indicating which of them will be
`crucial to