Pre Formulas i
Short Description
pharm...
Description
Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph.D Department of Pharmaceutics KLE University College of Pharmacy BELGUM!"#$$%$, Karnata&a, 'n(ia. Cell )o.* $$#% #+-%$$$ E!mail* nan/0a(e1&2gmail. n an/0a(e1&2gmail.com com 04/05/2012
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CONTENTS 3 'ntro(uction 3 4rganoleptic properties 3 Purity 3 Particle si5e, shape an( surface area 3 6olu1ilisation, 6urfactants an( its importance 3 7emperature, p8, co!solvency, soli( (ispersion, 9! cyclo(e:trin (rug!(ispersion system 3 Preformulation sta1ility stu(ies 3 consi(eration of physico!chemical characteristics of ne0 (rug molecules 0ith respect to (ifferent (osage forms 04/05/2012
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Preformulation 3 Preformulation is 1ranch of Pharmaceutical science that utili5es 1iopharmaceutical principles in the (etermination of physicochemical properties of the (rug su1stance. 3 Prior to the (evelopment of any (osage form ne0 (rug , it is essential that certain fun(amental physical ; chemical properties of (rug po0(er are (etermine( . 3 7his information may (ictate many of su1se ii. Coarse =H-$> iii. Mo(erately coarse =H$> iv. @ine =HJ$> v. ery fine =HI$>
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P"RTIC#E SI*E 3 Particle si5e can influence variety of important factors * ! Dissolution rate ! 6uspen(a1ility ! Uniform (istri1ution ! Penetra1ility ! Lac& of grittiness 04/05/2012
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%et+ods to Determine Partile Si,e
3 6ieving 3 Microscopy 3 6e(imentation rate metho( 3 Light energy (iffraction 3 Laser holography 3 Casca(e impaction 04/05/2012
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%et+ods to Determine Partile Si,e -. 3 3 3
Sievin met+od ' ange * "$ ? %"$ m 6imple, ine:pensive 'f po0(er is not (ry, the apertures get clogge(. /. %iroso0& ' 3 ange * $.- ? %$$ m 3 Particle si5e can 1e (etermine( 1y the use of cali1rate( gri( 1ac&groun(. 3 Most (irect metho(. 3 6lo0 ; te(ious metho(. 04/05/2012
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%et+ods to Determine Partile Si,e 1. 3 3 3
Sedimentation met+od ' ange * % ! -$$ m n(reasen pipette is use(. Particle si5e is calculate( 1y sto&es la0 *
1- 0 h
&#$
(ρs -ρ0) gt
here, h (istance of fall in time, t no viscosity of the me(ium s (ensity of the particles 04/05/2012
$ (ensity of the (ispersion me(ium KLE College of Pharmacy, Nipani.
acceleration (ue
gravity
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%et+ods to Determine Partile Si,e 2. 3 3
3 3. 3 3
#i+t ener& diffration ' ange * $." ? "$$ m Particle si5e is (etermine( 1y the re(uction in light reaching the sensor as the particle, (isperse( in a liueous solution of a soa0 or deterent in w+i+ a t+ermod&namiall& sta:le solution is formed ?.
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It is t+e 0roess :& w+i+ a00arent solu:ilit& of an ot+erwise s0arinl& solu:le su:stane is inreased :& t+e 0resene of surfatant mielles .
MICELLES: -
T+e me+anism involves t+e 0ro0ert& of surfae ative aents to form olloidal areates @nown as mielles . 04/05/2012
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4+en surfatants are added to t+e li>uid at low
onentration t+e& tend to orient at t+e air(li>uid interfae . On furt+er
addition of surfatant t+e interfae :eomes om0letel& ou0ied and e6ess moleules are fored into t+e :ul@ of li>uid. "t ver& +i+ onentration surfatant moleules in
t+e :ul@ of li>uid :ein to form mielles and t+is onentration is @now as CRITICAL MICELLE CONCENTRATION {CMC} 04/05/2012
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Solu:ili,ation is t+ou+t to our :& virtue of t+e
solute dissolvin in or mielle.
:ein adsor:ed
onto t+e
T+us t+e a:ilit& of surfatant solution to dissolved or solu:ili,e water insolu:le materials starts at t+e C%C and inrease wit+ inrease in t+e onentration of mielles.
Solu:ili,ation of an& material in an& solvent de0ends on 0ro0er seletion of solu:ilisin aents. 04/05/2012
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T+e 0roess of solu:ili,ation involves t+e :rea@in
of inter(ioni or intermoleular :onds in t+e soluteA t+e se0aration of t+e moleules of t+e solvent to 0rovide s0ae in t+e solvent for t+e soluteA interation :etween t+e solvent and t+e solute moleule or ion. Ste0 -' 7oles o0ens in t+e solvent
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Ste0/' %oleules of t+e solid :rea@s awa& from t+e :ul@
Ste0 1' T+e free solid moleule is interraded into t+e +ole in t+e solvent
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T+e amount of su:stane t+at 0asses into solution in order to esta:lis+ e>uili:rium at onstant tem0erature and 0ressure to 0rodue a saturated solution.
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If solu:ilit& is -mml indiates need for salt
formation to im0rove solu:ilit&. If
solu:ilit& is -mml in 07 0reformulation stud& s+ould :e initiated.
-
to
A
Solu:ilit& s+ould ideall& :e measured at two
tem0eratures' 2FC and 1FC. 2FC to ensure P+&sial sta:ilit&. 1FC to su00ort Bio0+armaeutial evaluation. 04/05/2012
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Desc"iption
&a"ts o sol'ent "ei"ed o" one pa"t o solte
7ery #ol'le Areely #ol'le Bol'le Bparingly #ol'le Bligh$ly #ol'le 7ery #ligh$ly #ol'le !n#ol'le
1 1 10 10 30 30 100 100 1000
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1000 10,000 6 10,000
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Preformulation solu:ilit& studies fous on dru solvent s&stem t+at ould our durin t+e deliver& of dru andidate. $or e.. " dru for oral administration s+ould :e
e6amined for solu:ilit& in media +avin isotoni +loride ion onentration and aidi 07.
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"nal&ti met+od t+at are 0artiularl& useful
for solu:ilit& measurement inlude 7P#CA U= s0etroso0&A $luoresene s0etroso0& and !as +romatora0+&.
Reverse 0+ase 7P#C offer aurate and effiient mean of olletin solu:ilit& data of dru.
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Ionization constant (pKa) Can :e alulated :& 7enderson 7assel:a+ e>uation( $or aidi drusG.07 0KaH lo ioni,ed druJ unioni,ed druJ
$or :asi drusG.07 0KaH lounioni,ed druJ ioni,ed druJ
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pH Soluilit! "#o$il% T+e solu:ilit& of aidi or :asi dru will s+ow
differene in solu:ilit& wit+ +anes in 07.
07 solu:ilit& 0rofile of a dru an :e esta:lis+ed :& runnin t+e e>uili:rium solu:ilit& e60eriment wit+in 07 rane of 1(2.
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"a#tition Co%$$ici%nt It is t+e ratio of unioni,ed dru distri:uted
:etween orani and a>ueous 0+ase at e>uili:rium.
P o0 = C oil C 0ater >euantit& of solvent. Endot+ermi reation E6ot+ermi reation
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Determination of solubility
The following points should be considered
The solvent & solute must be pure.
A saturated solution must be obtained before any solution is removed for analysis.
The method of separating a sample of saturated solution from undissolved solute must be satisfactory.
The method of analyzing solution must be reliable
Temperature must be adequately controlled .
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Solubility Determination Method
Solubility is normally depends on temperature so temperature is recorded in each solubility measurement. !lot of solubility against temperature is commonly used for solubility determination. Two methods are available for determination are as follow. ".Analytical method "".Synthetic method
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Analytical method
Temperature of equilibrium is fi#ed and concentration of the solute in the saturated solution is determined at equilibrium by a suitable analytical procedure.
"n other words a saturated solution in the presence of an e#cess of the undissolved solute is prepared at an accurately $nown temperature. This situation can be achieved by suitable contact b%w solute and solvent. 04/05/2012
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Synthetic method
"n this method a weighed amount of solute is placed in the vessel. hile agitating the system at constant temperature $nown amount of solvent is added gradually until the solubility limit is reached. At equilibrium temperature and content of the system is recorded. This method is carried out at micro scale level by e#amining the small amount of the system under hot stage microscope. 04/05/2012
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+eneral Method of "ncreasing the Solubility Addition
of co'solvent p( change method )eduction of particle size Temperature change method (ydotrophy Addition of Surfactant Dielectrical *onstant *omple#ation 04/05/2012
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Addition 0f *o'Solvent ea$ ,lectrolyte -' !henobarbitone on polar -' itro *ellulose These are poorly soluble in given solvent. /or such poorly soluble materials to enhance their solubility the water miscible solvents are used in which the drug has good solubility. This process of improving solubility is $nown as co'solvency and the solvent used is $nown as co' solvents. 04/05/2012
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Addition 0f *o'Solvent e.g. !henobarbitone is insoluble in water. A clear solution is obtained by dissolving in mi#ture of Alcohol +lycerin !ropylene glycol. e.g. Of Cosolvents:!+ glycerin sorbitol !,+ +lyceryl formal glycofurol ethyl carbamate ethyl lactate and dimethyl acetamide.
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p( change Method ea$
base-' Al$aloids 1ocal Anaesthesia ea$ acid-' Sulphonamides 2arbiturates
"n aqueous medium they dissociate poorly and undissociated portion is insoluble. e.g. 2enzoic acid !henobarbitone So solubility of the undissociated portion is improved by p( control. /or wea$ acidic drug-' increase p( solubility is increase. /or wea$ base drug-' decrease p( increase solubility. 04/05/2012
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)eduction 0f !article size
)eduction in !article size improve solubility of drug. 2asically
reduction in particle size increase contact surface area of the particle there by ultimately it increase rate of solubility of drug.
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Temperature *hange Method
"n endothermic reaction temperature solubility is increase.
by
increasing
"n
e#othermic reaction by increasing temperature solubility is decrease. e.g. Methyl *ellulose when mi#ed with water and temperature is raised it becomes insoluble. To dissolve it cold water is added. 04/05/2012
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(ydotrophy
The term (ydotrophy has been used to designate the increase in solubility in water of various substances due to the presences of large amount of additives. e.g. Solubilization of 2enzoic acid with Sodium benzoate.
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Addition of Surfactant Surfactants
are molecules with well defined polar and non'polar region that allow them to aggregate in solution to form micelles. on polar drugs can partition into micelles and be solubilized. e.g. Surfactant based solution of Ta#ol that is solubilized in 345 solution of *remophor.
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Dielectrical *onstant Dielectrical
*onstant is the effect that substances has when it acts as a solvent on the case with which it separates oppositely charged atoms. e.g. D,* of ater' 64 7erosene' 8 +lycerine' 96 2enzene' 8.8
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*omple#ation /or
the *omple#ation occur both drug and ligand molecule should be able to donate or accept electrons. The solubility of compound is the sum of solubility of the compound and its comple#. e.g. (g"8 :Mercuric "odide; is sparingly soluble in water. "ts solubility in water is increased by forming comple# with 7". (g"8 dried at o ' c. The dried mass is pulverized and sieved through "##G. &g. Fimesulide , meprazole
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Co(e!aporation method • In this method, a. solution of b(cyclodextrin is added to an alcoholic solution of drug. • The resulting mix. is stirred for " hr. > evaporated at o ' c until it is dried. • The dried mass is pulverized and sieved through "##G. • &g. +teroids > $iclofenac sodium 04/05/2012
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Solid dispersion method • Here the drug > molar ty. of b(cyclodextrin is dissolved in methanol. • The solution is then evaporated in vacuum at '# oc with rotatory evaporator. • The powder is stored under vacuum in dessicator for B days > analysed. • &g. 5ifampicin 04/05/2012
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+pray drying method • In this, the drug > double molar of (cyclodextrin are dissolved in methanol. • The solution was then spray dried under foll. conditions : )eed rate : "# mlCmin o Inlet temp. ( J c o utlet temp. ( 7 c Press. : bar B $rying air : B m
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+pray drying method • The powder is then collected > stored under vacuum in dessicator for B days > analysed. • &g. Faproxene
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5eutrali6ation method • Here the drug > b(cyclodextrin are dissolved in #."F H%l > then #."F FaH is added to precipitate the complex at pH(@.. • The ppt. is washed with distilled water. • Then it is pulverized > sieved through J#G and stored in dessicator over fused %a%l D. • &g. Eetoconazole 04/05/2012
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Applications • To increase a. solubility • To increase dissolution rate of drug • To improve bioavailability of drug • To increase chemicalCphysical stability • To decrease drug irritation
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Crystallinity • %rystal habit > internal structure of drug can affect bul/ > physicochemical property of molecule. • %rystal habit is description of outer appearance of crystal. • Internal structure is molecular arrangement within the solid.
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Crystallinity • %hange with internal structure usually alters crystal habit. &g. %onversion of sodium salt to its free acid form produce both change in internal structure > crystal habit.
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Different shapes of crystals • Cu0ic or isometric ( not always cube shaped. !lso find as octahedrons 2eight faces1 and dodecahedrons 2"# faces1. • %etragonal( similar to cubic crystals, but longer along one axis than the other, forming double pyramids and prisms. • 7rthorhom0ic ( li/e tetragonal crystals except not suare in cross section 2when viewing the crystal on end1, forming rhombic prisms or dipyramids 2two pyramids stuc/ together1. 04/05/2012
• $exagonal ( six(sided prisms. 0hen you loo/ at the crystal on(end, the cross section is a hexagon. • %rigonal ( possess a single B(fold axis of rotation instead of the 7(fold axis of the hexagonal division. • %riclinic ( usually not symmetrical from one side to the other, which can lead to some fairly strange shapes. • Monoclinic ( li/e s/ewed tetragonal crystals, often forming prisms and double pyramids.
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Different shapes of crystals
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Different shapes of crystals • $epending on internal structure compounds is classified as ". %rystalline D. !morphous • %rystalline compounds are characterized by repetitious spacing of constituent atom or molecule in three dimensional array. • In amorphous form atom or molecule are randomly placed.
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Different shapes of crystals • +olubility > dissolution rate are greater for amorphous form then crystalline, as amorphous form has higher thermodynamic energy. &g. !morphous form of Fovobiocin is well absorbed whereas crystalline form results in poor absorption.
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Polymorphism • It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice. • $ifferent crystalline forms are called polymorphs. • Polymorphs are of D types ". &natiotropic D. *onotropic
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Polymorphism • The polymorph which can be changed from one form into another by varying temp. or pressure is called as &nantiotropic polymorph. &g. +ulfur. • ne polymorph which is unstable at all temp. > pressure is called as *onotropic polymorph. &g. lyceryl stearate.
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Polymorphism • Polymorph differ from each other with respect to their physical property such as
+olubility *elting point
$ensity
Hardness %ompression characteristic
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Polymorphism • $uring preformulation it is important to identify the polymorph that is stable at at room temp. &g. "1%hloromphenicol exist in !,? > % forms, of these ? form is more stable > most preferable. D15iboflavin has I,II > III forms, the III form shows D# times more water solubility than form I. 04/05/2012
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%echni3ues for studies of %echni3ues crystals • *icroscopy • Hot stage microscopy • Thermal analysis • 4(ray diffraction
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Microscopy • Material with more than one refractive index are anisotropic & appear bright with brilliant colors against black polarized background. • The color intensity depends upon crystal thickness. • Isotropic material have single refractive index and this substance do not transmit light with crossed polarizing filter and appears appears black.
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Microscopy • dvantage ! "y this method# we can study crystal morphology & difference between polymorphic form. • $isadvantage ! This re%uire a well trained optical crystallographer# as there are many possible crystal habit & their appearance at different orientation.
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Hot stage microscopy • The polarizing microscope fitted with hot stage is useful for investigating polymorphism# melting point & transition temp. • $isadvantage ! In this techni%ue# the molecules can degrade during the melting process.
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Hot stage microscopy • $iagramma#ic repre!en#a#ion
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• e!"l#! of ho# !#age micro!copy
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Thermal analysis • $ifferential scanning calorimetry $'() $ifferential thermal analysis are $T) particularly useful in the investigation polymorphism.
& are of
• It measures the heat loss or gain resulting from physical or chemical changes within a sample as a function of temp.
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Thermal analysis • *or characterizing crystal forms # the heat of fusion can be obtained from the area under $'(+ curve for melting endotherms. • 'imilarly# heat of transition from one polymorph to another may be calculated. • sharp symmetric melting endotherm can indicate relative purity of molecule.
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Thermal analysis • broad asymmetric curve indicates presence of impurities. • $isadvantage ! $egradation during thermal analysis may provide misleading results.
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X-ray diffraction • ,orking ! ,hen beam of nonhomogenous -+ray is allow to pass through the crystal# -+ray beam is diffracted & it is recorded by means of photographic plate. • $iffraction is due to crystal which acts as dimensional diffraction grating toward -+ray.
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X-ray diffraction
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X-ray diffraction • /andom orientation of crystal lattice in the powder causes the -+ray to scatter in a reproducible pattern of peak intensities. • The diffraction pattern is characteristic of a specific crystalline lattice for a given compound .
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X-ray diffraction • n amorphous form does not produce a pattern mixture of different crystalline forms.
• 'ingle 0 (rystal x+ray provide the most complete information about the solid state.
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Stability testing….
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Why Stability? • 1rovide a evidence on how the %uality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as2.. temperature# 3umidity and light. • 4stablish a re+test period for the drug substance or a shelf life for the drug product and recommended storage conditions. • "ecause physical# chemical or microbiological changes might impact the efficiency and security of the final product 04/05/2012 KLE College of Pharmacy, Nipani. 166
Where and Why? Stability Studies are preformed on ...
• Drug Substances DS! The unformulated drug substance that may subse%uently be formulated with excipients to produce the dosage form. • Drug "roducts D"! The dosage form in the final immediate packaging intended for marketing22. • controlled and documented determination of acceptable changes of the drug substance or drug product 04/05/2012
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What are changes? • 1hysical changes • ppearance • Melting point • (larity and color of solution • moisture • (rystal modification 1olymorphism) • 1article size • (hemical changes • Increase in $egradation • $ecrease of ssay • Microbial changes 04/05/2012
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#orced degradation studies • cidic & "asic conditions. • $ry heat exposure • 56 radiation exposure • Influence of p3 • Influence of temperature • Influence of ionic strength 04/05/2012
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$rrhenius %&uation • K ) *e+,a /here.. ) !pecific ra#e of egraa#ion. ) ga! con!#an# 1.'&% calorie! egree +1mole - ) a3!ol"#e #empera#"re. * ) fre"ency fac#or. Logarithmically ,
ln ) +a/ - ln * converting to log
10
Log ) +a/2.(0( .1/- log * log ) !pecific ra#e of egraa#ion * ) con!#an# 04/05/2012
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$rrhenius %&uation •
Plo# of log K 7/! 1/-8.yiel! a !lope e"al #o +a/2.(0( 8.. 9rom hich hea# of ac#i7a#ion a can 3e calc"la#e.
•
Log 2/1 ) a/2.(0( . -2 : -1 / -2.-1
Mean Kinetic Temperature
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Mean 'inetic Temperature /
• - ) +ln e : $- 1 e + / - 8. e+ / 2
n
n - ) ;ean ine#ic #emp ) ea# of ac#i7a#ion &(.144 Ki!co!i#y : Par#icle !iFe i!#ri3"#ion for oral !"!pen!ion! only Chemical proper#ie! : !!ay : $egraa#ion pro"c#! : $egraa#ion pre!er7a#i7e! : Con#en# an#ioBian#! ;icro3ial proper#ie! Con#ainer clo!"re !y!#em proper#ie! : 9"nc#ionali#y #e!#!
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•
•
• •
Testing scope for LIQUID FORMS for in+. and PARENTRAL
Phy!ical+chemical proper#ie! : p : Lo!! on eigh# : Color @ clari#y of !ol"#ion Chemical proper#ie! : !!ay : $egraa#ion pro"c#! : $egraa#ion pre!er7a#i7e! : Con#en# an#ioBian#! ;icro3ial proper#ie! Con#ainer clo!"re !y!#em proper#ie! : 9"nc#ionali#y #e!#!
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Testing scope for SEMI LIQUID FORMS • Phy!ical+chemical proper#ie! : ppearance, oor, homogene!i#y, con!i!#ency : Lo!! on eigh#, >i!co!i#y : Con#en# "niformi#y i#hin #he con#ainer • Chemical proper#ie! : !!ay : $egraa#ion pro"c#! @ pre!er7a#i7e! : Con#en# pre!er7a#i7e! : $egraa#ion: Con#en# an#ioBian#! • ;icro3ial proper#ie! •
Con#ainer clo!"re !y!#em proper#ie! : 9"nc#ionali#y #e!#!
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(limatic ,ones Storage conditions &limatic 4one Co"n#rie!
Clima#ic Hone I-empera#eI =uropean &ommission =uropean )nion " =#/> =uropean eeration o! #harmaceutical nustries an
/ssociations
" MHLW> Ministry o! Health, Labor an Wel!are, @apan " @#M/> @apan #harmaceutical Manu!acturers /ssociation " +/> )S oo an +rug /ministration " #h-M/> #harmaceutical -esearch an Manu!acturers o! /merica
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• There are aitionally observers installe to act as a lin< Aith non&H countries an regions • M • -he E"ropean 9ree -rae rea E9-, repre!en#e 3y *i!!meic *i#Ferlan • eal#h Canaa Olo3al g"ieline!
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(H 0uidelines • A"ali#y "ieline! BQ chemical an pharmace"#ical A : e#ail! !ee neB# !lie • *afe#y "ieline! SQ in 7i#ro an in 7i7o pre+clinical !#"ie! : co7ering Carcinogenici#y -e!#ing, eno#oBici#y -e!#ing, -oBicoine#ic! an Pharmacoine#ic! 8.. e#c. • Efficacy "ieline! =Q clinical !#"ie! in h"man !"3Rec# : Co7ering clinical !afe#y, $o!e e!pon!e *#"ie!, oo Clinical Prac#ice!, Clinical e7al"a#ion 8. e#c. • ;"l#ii!ciplinary "ieline! MQ : Co7ering ;eical -erminology, Elec#ronic *#anar! for -ran!mi!!ion of eg"la#ory Jnforma#ion 88 e#c. : Jmpor#an# for *#a3ili#y S T "ieline M7U -he Common -echnical $oc"men# C-$ 04/05/2012
KLE College of Pharmacy, Nipani.
1&6
(H 1-0uidelines 1uality! • • • • • • • • • •
'tability Testing in (limatic :one I and II ;
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