Solids - Pharmaceutical Press
Physicochemical Principles of PharmacyChapter No. 1 Dated: 26/7/2011 At Time: 10:20:161Solids1.1 Classification of solids81.7 Wetting of powders311.2 Crystalline solids – structure and properties81.8 Sublimation341.9 Solid dispersions381.3 Amorphous solids251.4 Dissolution of solid drugs261.5 Importance of particle size in the formulationand manufacture of solid dosage forms281.6 Biopharmaceutical importance of particle size29Summary41References42The physical properties of the solid state seen in crystals and powders of both drugs and pharmaceuticalexcipients are of interest because they can affect both the production of dosage forms and the performanceof the finished product. Powders, as Pilpel1 reminded us, ‘can float like a gas or flow like a liquid’ butwhen compressed can support a weight. Fine powders dispersed as suspensions in liquids are used ininjections and aerosol formulations. Both liquid and dry powder aerosols are available and are discussedin Chapter 10. In this chapter we deal with the form and particle size of crystalline and amorphous drugsand the effect these characteristics have on drug behaviour, especially on drug dissolution andbioavailability.Crystalline solids can exist in several subphases, such as polymorphs, solvates, hydrates, and cocrystals. Polymorphs are different crystalline forms (at different free energy states) of the same molecule ormolecules. On the other hand, solvates, hydrates and co-crystals are similar in that they consist of morethan one type of molecule, one of which is the drug while the other can be either an organic solvent (toform a solvate) or water (to form a hydrate), or another crystalline solid (to form co-crystals). Both typesof molecules participate in the short-range and long-range orders of the crystal and therefore thesesubphases are regarded as single crystalline forms consisting of two types of molecules.The nature of the crystalline form of a drug substance may affect its stability in the solid state, itssolution properties and its absorption. It is with this topic that we start, to consider later other propertiesof the solid state that are important in production and formulation. Recently, nanocrystals of poorlysoluble drugs have been produced to improve their dissolution and absorption.Sample chapter from Physicochemical Principles of Pharmacy
Physicochemical Principles of PharmacyChapter No. 1 Dated: 26/7/2011 At Time: 10:20:168 Physicochemical Principles of Pharmacy1.1 Classification of solidsNaClThe solid phase can be classified into two majorcategories based on the order of molecular packing.The most common type of state is the crystalline statein which there is both short-range and long-rangeorder; that is, there is a regular structure that extendsthroughout the crystal. This contrasts with amorphous solids in which the regularity of structure islimited to the immediate neighbours of any particular molecule within the solid. Crystalline solids canbe further subdivided as shown in Fig. 1.1 into polymorphs, which result from different crystallineforms of the same molecule, and multicomponentcrystals such as hydrates, solvates and co-crystals,which consist of more than one type of type ofmolecule.1.2 Crystalline solids – structureand properties1.2.1 Crystal structureCrystals contain highly ordered arrays of moleculesand atoms held together by non-covalent interactions. We can consider as a simple example the unitcell of an inorganic salt, sodium chloride. Figure 1.2shows the ordered arrangement of Cl ions and Naþions that make up the sodium chloride crystal structure. We can draw a square on one side connectingthe chloride ions. Similar squares could be drawn onall the sides to form a cubic repeating unit, which wecall the unit cell. Within a specific crystal, each unitcell is the same size and contains the same numberof molecules or ions arranged in the same way. ItClSolidCrystalSolvates andhydratesCo-crystalsFigure 1.1Classification of aClFigure 1.2 Space lattice of the sodium chloride crystal. Eachsodium ion is octahedrally surrounded by six chloride ions andeach chloride ion is octahedrally surrounded by six sodiumions.is usually most convenient to think of the atoms ormolecules as points and the crystal as a threedimensional array of these points, or a crystallattice.For all possible crystals there are seven basic orprimitive unit cells, which are shown in Fig. 1.3. Wewill represent the lengths of the sides as a, b and c andthe angles asa (between sides b and c)b (between sides a and c)g (between sides a and b)Figure 1.3 shows the characteristic side lengths andangles for these ‘primitive’ unit cells.The structures in Fig. 1.3 have atoms or moleculesonly at each corner of the unit cell. It is possible tofind unit cells with atoms or molecules also at thecentre of the top or bottom faces (end-centred),at the centre of every face (face-centred) or with asingle atom in the centre of the cell (body-centred), asin Fig. 1.4.Note that these variations do not occur with everytype of unit cell: we find*PolymorphsNaClCl*Amorphous formClNa*End-centred monoclinic and orthorhombicFace-centred cubic and orthorhombicBody-centred, cubic, tetragonal andorthorhombicAltogether there are 14 possible types of unit cell andwe call these the Bravais lattices. For drugs there arethree common types of unit cell: triclinic, monoclinicand orthorhombic.Sample chapter from Physicochemical Principles of Pharmacy
Physicochemical Principles of PharmacyChapter No. 1 Dated: 26/7/2011 At Time: 10:20:16Solids 9aaabc 90aCubicab b aa a120Hexagonal120a c90 cc 90 but120abc 90baOrthorhombic c 90c acaaTetragonal90b Trigonalccba aa baMonoclinicc abc baTriclinicFigure 1.3 The seven possible primitive unit cells with atoms or molecules only at each corner of the unit cell. Drug molecules willtypically form triclinic, monoclinic and orthorhombic unit cells.Key CubicFigure 1.4caaTetragonalacbOrthorhombic*The crystal lattice is constructed fromrepeating units called unit cells; all unitcells in a specific crystal are the same sizeand contain the same number of moleculesor ions arranged in the same way.There are seven primitive unit cells – cubic,trigonal, orthorhombic, triclinic,hexagonal, tetragonal and monoclinicwhich have molecules or ions arranged ateach corner.In addition, monoclinic and orthorhombicunit cells may be end-centred; cubic andorthorhombic unit cells may be facecentred; and cubic, tetragonal andorthorhombic unit cells may be bodycentred.There are therefore only 14 possible types– the Bravais lattices.Drug molecules usually have triclinic,monoclinic or orthorhombic unit cells.Variations on primitive cells.Sample chapter from Physicochemical Principles of Pharmacy
Physicochemical Principles of PharmacyChapter No. 1 Dated: 26/7/2011 At Time: 10:20:1610 Physicochemical Principles of PharmacyMiller indicesWe can identify the various planes of a crystal usingthe system of Miller indices. To understand how thissystem is used, let us consider the plane drawnthrough the cubic crystal shown in Fig. 1.5a. Theplane cuts the a axis at one unit length and also thec axis at one unit length. It does not, however, cut theb axis, and hence the intercept to this axis is infinity.One way we could label planes is to denote each setby the distances along the axes to the point where theplane crosses the axis. So, for example, the planesmarked in Fig. 1.5a would have intercept lengths ofa ¼ 1, b ¼ , c ¼ 1. This system of labelling the faces isinconvenient because of the appearance of . A wayaround this problem is to take the reciprocals of thenumbers (since the reciprocal of ¼ 0). The planeshown then becomes 1/1, 1/ , 1/1 for the a, b and caxes, i.e. 1, 0, 1. The Miller indices for this plane arethen written as (101).A second example is illustrated in Fig. 1.5b. Thisplane does not cut the a axis; it cuts the b axis at a unitcell length of 12, and does not cut the c axis. Theintercept lengths are therefore a ¼ , b ¼ 12, c ¼ ,which on taking reciprocals become 0, 2, 0. A secondrule of Miller indices is now applied, that is to reducethe numbers to the lowest terms – in this case bydividing them all by 2. The Miller indices for thisplane are therefore (010).Other rules for applying Miller indices are shownby the following examples, which for ease of illustration are shown using a two-dimensional array (thec axis can be imagined to be at right angles to thepage). None of the sets of planes we will considercrosses the c axis, i.e. we consider them to intersect itat . The plane X in Fig. 1.6 has a, b and c interceptsof 3, 2, and , giving reciprocals of 13, 12 and 0. Theprocedure is now to clear the fractions, in this case bymultiplying each term by 6, giving 2, 3, and 0. It isnot possible to reduce these further, and the Millerindices are therefore (230). The plane Y in Fig. 1.6shows an example of a negative intercept where the aaxis is crossed. The reciprocals of the a, b and cintercepts are 1, 1, and 0. The procedure that isnow used is to write the negative number using abar above it, giving Miller indices for this plane of(110). We should notice that the smaller the numberin the Miller index for a particular axis, the moreparallel is the plane to that axis, a zero value indicating a plane exactly parallel to that axis. The larger aMiller index, the more nearly perpendicular a planeis to that axis.b101 Planeacb(a)Y (110)bX0.5b010 Planeaca(b)Figure 1.5 Cubic crystal showing planes with Miller indices of(a) (101) and (b) (010).YFigure 1.6X (230)Planes in a two-dimensional array.Sample chapter from Physicochemical Principles of Pharmacy
Physicochemical Principles of PharmacyChapter No. 1 Dated: 26/7/2011 At Time: 10:20:16Solids 11Key pointsThe general rules for expressing planes usingthe system of Miller indices:*****Determine the intercepts of the plane onthe a, b and c axes in terms of unit celllengths.Take the reciprocals of the intercepts.Clear the fractions by multiplying by thelowest common denominator.Reduce the numbers to the lowest terms.Indicate negative numbers with a barabove the number.Example 1.1 Use of Miller indicesDraw a two-dimensional lattice array and indicate the planes with the following Miller indices:(i) (100); (ii) (010); (iii) (110); (iv) (120); (v)(230); and (vi) (410).Answer(230)(120)(010)(110)filtration, flow, tableting, dissolution and bioavailability. These are described below. In addition, crystallisation can sometimes occur in vivo, often, as in thecase of gout (see below), with painful consequences.The crystals of a given substance may vary in size,the relative development of the given faces and thenumber and kind of the faces (or forms) present; thatis, they may have different crystal habits. The habitdescribes the overall shape of the crystal in rathergeneral terms and includes, for example, acicular(needle-like), prismatic, pyramidal, tabular, equant,columnar and lamellar types. Figure 1.8 shows thecrystal habits of a hexagonal crystal.Although there may not be significant differences inthe bioavailability of drugs with different crystal habits,the crystal habit is of importance from a technologicalpoint of view. The ability to inject a suspension containing a drug in crystal form will be influenced by thehabit: plate-like crystals are easier to inject through afine needle than are needle-like crystals. The crystalhabit can also influence the ease of compression of apowder and the flow properties of the drug in the solidstate. The plate-like crystals of tolbutamide, for example, cause powder bridging in the hopper of the tabletmachine and also capping problems during tableting.Neither of these problems occurs with tolbutamide inother crystal habits. The habits acquired depend on theconditions of crystallisation, such as the solvent used,the temperature, the concentration and presence ofimpurities. Ibuprofen crystallises from hexane as elongated needle-like crystals, which have been found tohave poor flow properties; crystallisation from methanol produces equidimensional crystals with better flowproperties and compaction characteristics, makingthem more suitable for tableting. The crystal morphology of the excipients (such as powdered cellulose)included in tablet formulations can also have a significant influence on the strength and disintegration timeof tablets.(100)(410)Crystallisation and factors affectingcrystal form21.2.2 Crystal formThe solid state is important for a variety of reasons,summarised in Fig. 1.7: morphology, particle size,polymorphism, solvation or hydration can affectCrystallisation from solution can be considered to bethe result of three successive processes:***Supersaturation of the solutionFormation of crystal nucleiCrystal growth round the nucleiSample chapter from Physicochemical Principles of Pharmacy
Physicochemical Principles of PharmacyChapter No. 1 Dated: 26/7/2011 At Time: 10:20:1612 Physicochemical Principles of PharmacyMorphology &Particle sizeFiltration processesCrystallisationProcessingBulk powder flowPolymorphism(e.g. milling,Dissolution ratesgrinding, oavailabilityhydrationFigure 1.7The solid state in pharmaceutical science: potential causes and effects of structural change (after A.J. Florence).Clinical point Gout – a painful example of crystallisationGout usually manifests itself as a sudden excruciating pain in the big toe (usually of men), although otherjoints such as the ankle, heel, instep, knee, wrist, elbow, fingers or spine may be affected. It is aconsequence of the precipitation of needle-like crystals of uric acid, in the form of monosodium urate,on the articular cartilage of joints when the levels of uric acid in blood serum exceed a critical solubilitylevel (approximately 6.7 mg/dL); the crystals inside the joint cause intense pain whenever the affected areais moved. Uric acid is a normal component of blood serum and is a product of the metabolism of purines,which are generated by the body via breakdown of cells in normal cellular turnover, and also are ingestedas part of a normal diet in foods such as liver, sardines, anchovies and dried peas and beans. The uric acidis normally filtered out of the blood by the kidneys and excreted in the urine. Sometimes, however, toomuch uric acid is produced by the body or the kidneys are not sufficiently efficient at removing it and itaccumulates in the blood, a condition known as hyperuricaemia. Precipitation of uric acid is alsomarkedly enhanced when the blood pH is low (acidosis), a consequence of reduced solubility under suchconditions. Patients with long-standing hyperuricaemia can have uric acid crystal deposits called tophi inother tissues such as the helix of the ear. High levels of uric acid in the urine can lead to uric acid crystalsprecipitating in the kidneys or bladder, forming uric acid kidney stones.Supersaturation can be achieved by cooling, by evaporation, by the addition of a precipitant or by a chemical reaction that changes the nature of the solute.Supersaturation itself is insufficient to cause crystalsTabularFigure 1.8to form; the crystal embryos must form by collision ofmolecules of solute in the solution, or sometimes bythe addition of seed crystals, or dust particles, or evenparticles from container walls. Deliberate seeding isPrismaticAcicularCrystal habits of a hexagonal crystal.Sample chapter from Physicochemical Principles of Pharmacy
Physicochemical Principles of PharmacyChapter No. 1 Dated: 26/7/2011 At Time: 10:20:17Solids 13often carried out in industrial processes; seed crystalsdo not necessarily have to be of the substance concerned but may be isomorphous substances (i.e. of thesame morphology). As soon as stable nuclei areformed, they begin to grow into visible crystals.Crystal growth can be considered to be a reversedissolution process and the diffusion theories of Noyesand Whitney, and of Nernst, consider that matter isdeposited continuously on a crystal face at a rate proportional to the difference of concentration betweenthe surface and the bulk solution. Thus an equation forcrystallisation can be proposed in the formdm¼ Akm ðcss cs Þdtð1:1Þwhere m is the mass of solid deposited in time t, A is thesurface area of the crystal, cs is the solute concentration atsaturation and css is the solute concentration at supersaturation. As km ¼ D/d (D being the diffusion coefficient ofthe solute and d the diffusion layer thickness; see Fig.1.18), the degree of agitation of the system, which affectsd, also influences crystal growth. Crystals generally dissolve faster than they grow, so growth is not simply thereverse of dissolution. It has been suggested that there aretwo steps involved in growth in addition to those mentioned earlier, namely transport of the molecules to thesurfaceandtheir arrangementinanorderedfashioninthelattice. Equation (1.1) turns out to be better written in amodified form:dm¼ Akg ðcss cs Þndtð1:2Þkg being the overall crystal growth coefficient and nthe ‘order’ of the crystal growth process. For moredetails reference 2 should be consulted.PrecipitationPrecipitation may be induced by altering the pH of thesolution so that the saturation solubility is exceeded.Precipitation may be made to occur from a homogeneous solution by slowly generating the precipitatingagent by means of a chemical reaction, a process likelyto occur, for example, in intravenous infusion fluidsand liquid pharmaceuticals. Precipitation by directmixing of two reacting solutions sometimes does notbring about immediate nucleation and, as a result, themixing stage may be followed by an appreciable lagtime. The rate of precipitation is an important factor indetermining habit, as might be imagined with adynamic process such as crystallisation, involvingnucleation and subsequent crystal growth. The formof phenylsalicylate, for example, depends on rate ofcrystal growth. Transition to an acicular shape occurswhen the rate of growth increases. At low rates ofgrowth, crystals of a more regular shape are obtained.In studies of the effect of solvents on habit it is generally found that less-viscous media favour the growthof coarse and more equidimensional crystal forms.Habit modificationCrystal habit can be modified by adding impurities or‘poisons’; for example, sulfonic acid dyes alter thecrystal habit of ammonium, sodium and potassiumnitrates.Surfactants in the solvent medium used for crystal growth (or, for example, in stabilisation or wetting of suspensions) can alter crystal form byadsorbing onto growing faces during crystal growth.This is best illustrated by the effect of anionic andcationic surfactants on the habit of adipic acid crystals.3 X-ray analysis showed that the linear sixcarbon dicarboxylic acid molecules were alignedend-to-end in a parallel array in the crystal with theirlong axis parallel to the (010) faces, so that the (001)face is made up entirely of COOH groups while the(010) and (110) faces contain both COOH andhydrocarbon (HC) portions of the molecule (Fig.1.9). The cationic surfactant trimethyldodecylammonium chloride is twice as effective in hinderingthe growth of the (001) face as that of the (110)and (010) faces. In high concentrations it causesthe formation of very thin plates or flakes.Conversely, the anionic surfactant sodium dodecylbenzene sulfonate at 55 ppm (parts per million) isthree times as effective in reducing the growth ratesof the (110) and (010) faces as of the (001) face.Higher levels of sodium dodecylbenzene sulfonatecause extreme habit modification, producing nothexagonal plates but long, thin rods or needles.The crystallographic faces whose growth rates aredepressed most are those upon which surfactantadsorption is the greatest. Cationic additives adsorbon the face composed of carboxylic groups (001),and anionic additives on the (110) and (010) faces,which are hydrophobic. A coulombic interaction of the cationic head groups and the COO groups onthe (001) faces has been suggested. The adsorption ofSample chapter from Physicochemical Principles of Pharmacy
Physicochemical Principles of PharmacyChapter No. 1 Dated: 26/7/2011 At Time: 10:20:1714 Physicochemical Principles of )'C'(110)'A'(010)'B'Adipic acid crystals(b)(001) face (anionic)COOHHC(110) face(hydrophobic)(010) face (hydrophobic)Figure 1.9 (a) Effect of anionic and cationic surfactants on the habit of adipic acid crystals. (b) A diagrammatic (not to scale)representation of the arrangement of molecules at the crystal surface.the anionic surfactant, repelled from the anionic(001) faces, takes place amphipathically on thehydrophobic (110) faces and (010) faces (Fig. 1.9).Key points***The crystal habit describes the externalappearance of a crystal, i.e. its overallshape and the number and kind of faces.Common types of habit include acicular,prismatic, pyramidal, tabular, equant,columnar and lamellar.The crystal habit depends on theconditions of crystallisation and mayaffect the syringeability of suspensions ofthe drug, its ease of compression intotablets and its flow properties.The crystal habit can be modified byadding impurities (called poisons) orsurfactants to the solvent used forcrystallisation.1.2.3 Polymorphism4As we have seen, compounds can crystallise out ofsolution in a variety of different habits depending onthe conditions of crystallisation. These crystal habitsusually have the same internal structure and so havethe same X-ray diffraction patterns. A more fundamental difference in properties may be found whenthe compounds crystallise as different polymorphs.When polymorphism occurs, the molecules arrangethemselves in two or more different ways in the crystal;either they may be packed differently in the crystallattice or there may be differences in the orientationor conformation of the molecules at the lattice sites.These variations cause differences in the X-ray diffraction patterns of the polymorphs and this technique isone of the main methods of detecting the existence ofpolymorphs. The polymorphs have different physicaland chemical properties; for example, they may havedifferent melting points and solubilities and they alsousually exist in different habits.We will consider two drugs that exhibit this phenomenon. Spironolactone (I), which is a diureticsteroidal aldosterone agonist, crystallises as two polymorphic forms and also as four solvated crystallineSample chapter from Physicochemical Principles of Pharmacy
Physicochemical Principles of PharmacyChapter No. 1 Dated: 26/7/2011 At Time: 10:20:17Solids 15forms depending on the solvents and methods used forcrystallisation.5 We will consider the occurrence ofsolvated forms in section 1.2.4; at the moment we willconcentrate on the two polymorphs only. Form 1 isproduced when spironolactone powder is dissolved inacetone at a temperature very close to the boiling pointand the solution is then cooled within a few hoursdown to 0 C. Form 2 is produced when the powderis dissolved in acetone, dioxane or chloroform at roomtemperature and the solvent is allowed to evaporatespontaneously over a period of several weeks. In bothpolymorphs the steroid nuclei (A, B, C and D rings) arealmost planar and perpendicular to the E ring and tothe 7a-acetothio side-chain. The packing of the molecules in the two polymorphs is compared in Fig. 1.10.Both unit cells are orthorhombic but they differ in theirdimensions. The a, b and c axes of Form 1 were foundto be 0.998, 3.557 and 0.623 nm, respectively, compared with equivalent lengths for Form 2 of 1.058,1.900 and 1.101 nm. There are also differences in thecrystal habits: Form 1 crystals are needle-like, whilethose of Form 2 are prisms (see Fig. 1.11). The meltingpoints are slightly different: Form 1 melts at 205 Cwhereas Form 2 has a melting point of 210 C.212220 E2618H3C19CH323O281A4119105B612C1314bbccaaForm 1Figure 1.10Form 2Unit cells of spironolactone.Reproduced with permission from reference 5.O25O17D 161587S2923O2724CH3Structure I SpironolactoneOur second example of a drug exhibiting polymorphism is paracetamol (II). This drug is known to existin two polymorphic forms, monoclinic (Form 1) andorthorhombic (Form 2), of which Form 1 is the morethermodynamically stable at room temperature and isthe commercially used form.6 However, this form is notsuitable for direct compression into tablets and has to bemixed with binding agents before tableting, a procedurethat is both costly and time-consuming. In contrast,Form 2 can readily undergo plastic deformation uponcompaction and it has been suggested that this formmay have distinct processing advantages over theForm 1Form 2Figure 1.11Crystal forms of spironolactone.Reproduced with permission from reference 5.Sample chapter from Physicochemical Principles of Pharmacy
Physicochemical Principles of PharmacyChapter No. 1 Dated: 26/7/2011 At Time: 10:20:1716 Physicochemical Principles of Pharmacymonoclinic form. Monoclinic paracetamol is readilyproduced by crystallisation from aqueous solutionand many other solvents; production of the orthorhombic form has proved more difficult but may be achieved,at least on a laboratory scale, by nucleating a supersaturated solution of paracetamol with seeds of Form 2(from melt-crystallised paracetamol). Figure 1.12shows scanning electron micrographs of the two polymorphic forms when crystallised from industrial methylated spirit (IMS). Form 1 is described as having aprismatic to plate-like habit that is elongated in thedirection of the c-axis, while Form 2 crystallises asprisms that are elongated along the c-axis.(a)HNHOCH3OStructure II ParacetamolPolymorphism is common with pharmaceuticalcompounds. Although we do not yet understand theprocess sufficiently well to predict which drugs arelikely to exhibit this phenomenon, it is clear that certain classes of drug are particularly susceptible. Eightcrystal modifications of phenobarbital have been isolated but 11 have been identified with melting pointsranging from 112 to 176 C. Of the barbiturates usedmedicinally, about 70% exhibit polymorphism. Thesteroids frequently possess polymorphic modifications, testosterone having four: these are cases of truepolymorphism and not pseudopolymorphism in whichsolvent is the cause (see section 1.2.4). Of the commercial sulfonamides, about 65% are found to exist inseveral polymorphic forms. Examples of the differingsolubilities and melting points of polymorphic sulfonamides and steroids are given in Table 1.1.Predictability of the phenomenon is difficultexcept by reference to past experience. Its pharmaceutical importance depends very much on the stabilityand solubility of the forms concerned. It is difficult,therefore, to generalise, except to say that where polymorphs of insoluble compounds occur there are likelyto be biopharmaceutical implications. Table 1.2 is apartial listing of the drugs for which polymorphic andpseudopolymorphic states have been identified or forwhich an amorphous state has been reported.Pharmaceutical implications of polymorphism(b)Figure 1.12 Scanning electron micrographs showing thecrystal habit of (a) Form 1 and (b) Form 2 of paracetamolgrown from supersaturated IMS. Note different scales.Reproduced with permission from reference 6.We have already considered the problems in tabletingand injection that may result from differences in crystal habit (see section 1.2.2). Since polymorphs frequently have different habits, they too will be subjectto these same problems. However, polymorphs alsohave different crystal lattices and consequently theirenergy contents may be sufficiently different to influence their stability and biopharmaceutical behaviour.As the different polymorphs arise through different arrangement of the molecules or ions in the lattice,they will have different interaction energies in the solidSample chapter from Physicochemical Principles of Pharmacy
Physicochemical Principles of PharmacyChapter No. 1 Dated: 26/7/2011 At Time: 10:20:18Solids 17Table 1.1 Melting points of some polymorphic forms of steroids, sulfonamides and riboflavinaCompoundForm and/or melting point ( C)Polymorphic 225223Testosterone155148144143MethylprednisoloneI (205, aqueous solubility 0.075 mg cm 3)II (230, aqueous solubility 0.16 mg cm 3)Polymorphic I (291, aqueous solubility 60 mg cm 3)II (278, aqueous solubility 80 mg cm 3)RiboflavinIII (183, aqueous solubility 1200 mg cm 3)aReproduced from Kuhnert-Brandstatter M, Thermomicroscopy in the Analysis of Pharmaceuticals, New York: Pergamon Press; 1971.Table 1.2 Polymorphic and pseudopolymorphic drugsaCompoundNumber of 1 1Beclometasone dipropionate 2Betamethasone11 Betamethasone 21-acetate11 Betamethasone 17-valerate11 Caffeine1 1Cefaloridine4 2Chloramphenicol palmitate31 (continued overleaf)Sample chapter from Physicochemical Principles of Pharmacy
Physicochemical Principles of PharmacyChapter No. 1 Dated: 26/7/2011 At Time: 10:20:1818 Physicochemical Principles of PharmacyTable 1.2 (continued)CompoundNumber of poxide HCl2 1Chlorthalidone2 Dehydropregnenolone1 7Dexamethasone acetate3 1Dexamethasone pivalate4 7Digoxin 1 Erythromycin2 Fludrocortisone acetate31 Fluprednisolone3 21 1Hydrocortisone TBA1 3Indometacin3Mefenamic acid2 Meprobamate2 Methyl p-hydroxybenzoate6 Methylprednisolone2 Novobiocin11 Prednisolone2 Prednisolone TBAb2 2c3 Prednisolone acetate2 Prednisone1 1Progesterone2 Sorbitol3 Testosterone4 Theophylline1 1Triamcinolone2
Solids 1.1 Classification of solids 8 1.2 Crystalline solids – structure and properties 8 1.3 Amorphous solids 25 1.4 Dissolution of solid drugs 26 1.5 Importance of particle size in the formulation and manufacture of solid dosage forms 28 1.6 Biopharmaceutical importance of particle size 29 1.7 Wetting of powders 31 1.8 Sublimation 34
1. Total solids (Standard Methods 2540B) 2. Total solids after screening with a 106 µm sieve 3. Total suspended solids (solids retained on a 0.45 µm filter) (Standard Methods 2540D) 4. Total Dissolved Solids (solids passing through a 0.45 µm filter) (Standard Methods 2540C) 5. Turbidity using a HACH 2100N Turbidimeter 6.
SDI sludge density index . SRT solids retention time . SS settleable solids . SSV. 30. settled sludge volume 30 minute . SVI sludge volume index . TOC total organic carbon . TS total solids . TSS total suspended solids . VS volatile solids . WAS waste activated sludge . Conversion Factors: 1 acre 43,560 square feet . 1 acre foot 326,000 .
Wire Processing Machine w/Press (WPM) or Bench Press only Panduit Applicators CA-800* CA-800EZ* CA9 PANDUIT CP-851 Bench Press only A CP-861 Bench Press only A CP-862 Bench Press only A1 CP-871 Bench Press only A1 AMP CLS III G w/G Press (WPM) A1 CLS IV w/G Press (WPM) A1 CLS IV Plus w/G Press (WPM) A1 G Bench Press only A1 CLS II w/T Press .
Demo Unit Turbidity . pile Pile Bounce. Equipment Settings: Control Panel . Calculations: lb/hr, lb/ton Ohaus . Screw Press Optimization 12.0 14.0 16.0 18.0 20.0 22.0 250 450 650 850 1050 1250 1450 1650) Solids Loading (lbs/hr) Cake Solids vs. Solids Loading . Screw Press Optimization . Screw Press Optimization .
bizhub PRESS C1100 bizhub PRESS C1085 bizhub PRESS C71hc bizhub PRESS C1070 bizhub PRESS C1070P bizhub PRESS C1060 bizhub PRO C1060L Digital B&W Presses bizhub PRESS 2250P bizhub PRESS 1250 bizhub PRESS 1250P bizhub PRESS 1052 bizhub PRO 1100 Bindery. Pro-quality options for every need. Sta
156 varun arora pharmaceutical organic chemistry –ii 157 devala rao inorganic pharmaceutical chemistry 158 siddiqui inorganic pharmaceutical chemistry 159 chatwal pharmaceutical chemistry inorganic 160 huneely inorganic chemistry 161 mohammed ali tb of pharmaceutical chemistry inorgan
Real Gases: Deviations from Ideal Behavior 184 11 LIquIDs AnD InTerMoLeCuLAr ForCes 193 A Molecular Comparison of Gases, Liquids, and Solids 193 Intermolecular Forces 196 Select Properties of Liquids 200 Phase Changes 201 Vapor Pressure 202 12 soLIDs AnD MoDern MATerIALs 211 Classification of Solids 211 Metallic Bonding 213 Ionic Solids 215
API Services describes functional areas exposed by the API. Audience, Purpose and Required Skills This guide is written for application developers. It assumes that you are a developer, and have a basic understanding of: How applications are developed in your environment. Functional understanding of the HTTP, JSON, and XML. Familiarity with Representational State Transfer (REST) architecture .
