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Samanta 1
CHAPTER – 1
Preformulation Studies
Syllabus:
Preformulation Studies: pKa and solu8bility, partition coefficient, crystal morphology, polymorphism, powder flow,
structure characteristics, dissolution, compatibility studies, protocol for pre-formulation..
Questions
Q1. Define polymorphism. [2]
Q2. Relevance of crystal morphology in solutions. [2]
Q3. Importance of powder flow in solid dosage form. [2]
Q4. Importance and application of dissolution.
Q5. Explain the importance of pKa and partition coefficient in the preformulation studies of liquid oral, solutions and
syrup dosage forms. Illustrate your answer with suitable examples. [10]
Preformulation
Preformulation may be described as a phase of the research and development process where the
preformulation scientist characterizes the physical, chemical and mechanical properties of a new drug
substance, in order to develop stable, safe and effective dosage form.
Objectives:
The preformulation investigations confirm that there are no significant barriers to the compound’s
development as a marketed drug. The formulation scientist uses these informations to develop dosage forms.
This is a reversible process. According to the law of mass action, the velocity or rate of forward reaction, Rf is
proportional to the concentrations of the reactants.
Rf = k1 x [HA] x [H2O]
or,
[
k1 H 3 O + A
=
][ ] 1000ml H2O has a mass of 997.07g
[see from density chart of H2O]
k 2 [HA][H 2 O ] 997.07
997.07g water = = 55.3moles water
In dilute solution water is in sufficient excess, so [H2O] can be 18.02
taken as constant. Therefore, [H2O] = 55.3 moles/lit = 55.3 M
or,
k1 [ +
[H 2 O ] = H 3 O A ][ ]
k2 [HA]
or, Ka =
[H O ][A ]
3
+
k1
[H 2 O]
where K a =
[HA] k2
Ka is called the ionization constant or dissociation constant or acidity constant of the weak acid HA.
[ H 3 O + ] [CH 3 COO ]
Therefore, Ka =
[CH 3 COOH ]
x2
=
c x
Since, c>>x the term c–x c
2
Therefore, Ka = x / c or, x = K a c or, [ H 3 O + ] = K a c
Problem: In a liter of a 0.1 M solution, acetic acid was found by conductivity analysis to dissociate into 1.32 x 10–3
gram ions (moles) each of hydrogen ion and acetate ion at 250C. What is the acidity constant, Ka for acetic
acid?
The Cl– is the conjugate base of the strong acid, HCl, which is 100% ionized in water. Thus Cl– cannot react any
further. According to Bronsted-Lowry system, NH4+ is considered to be a cationic acid and its conjugate base is NH3.
NH4+ + H2O H +
+3O + NH3
Acid 1 Base 2 Acid 2 Base 1
BPUT / M.Pharm. Sem-1 / Chapter-1 / Preformulation Studies / A. Samanta 3
[ H 3 O + ] [ NH 3 ]
In this case the acidity constant, Ka =
[ NH 4 + ]
H2O
Na+CH3COO Na+ + CH3COO
+
The Na ion cannot react with water (since it would form NaOH, which is a strong electrolyte and would dissociate
completely into ions.)
The acetate ion is a Bronsted-Lowry weak base, and
B + H 2O OH + HB
[OH ] [ HB]
Kb =
[B ]
Ionization of water
Just like weak acid or weak bases, water ionizes into hydrogen and hydroxyl ions. This auto protolytic reaction is
represented as
H2O + H2O H3O+ + OH
Acid 1 Base 2 Acid 2 Base 1
The law of mass action then applied to give the equilibrium expression:
[ H O + ] [OH ] [ H O + ] [OH ]
K = 3 or, K = 3 or, K [ H 2 O] 2 = [ H 3 O + ] [OH ]
[ H 2 O][ H 2 O] [ H 2 O] 2
Since, H2O is in large excess than H3O+ or OH– hence [H2O] can be takne as constant.
or, K [ H 2 O] 2 = cons tan t = K w
Kw is called dissociation constant, the autoprotolysis constant or the ion-product of water.
The value of Kw is approximately 1 x 10–14 at 250C. It depends strongly upon temperature.
In pure water, the hydrogen and hydroxyl ion concentrations are equal and [H3O+] = [OH–] = 1 x 10–7 M at 250C.
• When an acid is added to pure water the [H3O+] increases and [OH–] decreases but the ion-product of water, Kw,
remains constant.
• Under laboratory condition, distilled water in equilibrium with air contains about 0.03% by volume of CO2
corresponding to a [H3O+] of about 2 x 10–6 M (pH 5.7).
BPUT / M.Pharm. Sem-1 / Chapter-1 / Preformulation Studies / A. Samanta 4
HA + H 2O H3O+ + A A + H 2O HA + OH
=
[H O ][A ]
3
+
=
[HA][OH ]
Ka
[HA]
Kb
[A ]
Therefore, K a K b =
[H 3O ][A ] x [HA][OH ]
+
= [H3O+] [OH–] = Kw Therefore, K a K b = K w.
[HA] [A ]
Ionization of polyprotic electrolytes
Acids those donate a single proton and bases those accepts a single proton are called monoprotic electrolytes.
A polyprotic (polybasic) acid is one that is capable of donating two or more protons.
A diprotic (dibasic) acid is one that is capable of donating two or more protons.
An example of diprotic acid is carbonic acid:
+ [ HCO3 ] [ H 3 O + ]
H2CO3 + H2O HCO3 + H3O K1 =
[ H 2 CO3 ]
+ [CO3 2 ] [ H 3 O + ]
HCO3 + H2O CO32 + H3O K2 =
[ HCO3 ]
Example of a triprotic (tribasic) acid is phosphoric acid.
2 [ H 2 PO 4 ] [OH ] 7
K b2 = = 1.6 x 10
HPO 4 + H2O H2PO42 + OH [ HPO 4 2
]
[ H 3 PO 4 ] [OH ] 12
K b3 = = 1.3 x 10
H2PO4 + H2O H3PO4 + OH [ H 2 PO4 ]
Therefore K 1 K b1 = K 2 K b 2 = K 3 K b3 = K w
Ampholytes
A species that can function either as an acid or a s a base is called an ampholyte and is said to be amphoteric.
Example: If glycine hydrochloride is dissolved in water, it ionizes as follows:
+ H2O +
Cl H 3NCH2COOH H3NCH2COOH + Cl
+ + +
H3NCH2COOH + H2O H3NCH2COO + H3O
Acid Base
+ +
H3NCH2COO + H2O H2NCH2COO + H3O
Acid Base
H3N+CH2COO– is amphoteric in nature because it can act both as an acid and base with water as follows:
BPUT / M.Pharm. Sem-1 / Chapter-1 / Preformulation Studies / A. Samanta 5
+
H3NCH2COO + H2O H2NCH2COO + H3O+
Acid Base
+ +
H3NCH2COO + H2O H3NCH2COOH + OH
Base Acid
This type of species having two types of charges on one molecule are called zwitterions. The pH at which zwitterion
concentration is maximum is known as isoelectic point.
Determination of pKa
pKa of a drug molecule can be determined by various methods:
1. Potentiometric (pH) method
2. Spectrophotometric method
3. Partition-coefficient method
4. Conductometric method
5. Solubility method
Among all the methods potentiometric and spectrophotometri cmethods are most popular and accurate methods by
which the pKa are determined.
Step-1: An acid is dissolved in deionized water (100ml). The pH is determined with a previously calibrated pH-meter
(Potentiometer).
Step-2: The solution is titrated with N/10 NaOH solution. Each time 1ml NaOH solution is added.
Step-3: The pH versus volume of NaOH solution added is plotted. A titration curve will be obtained.
Step-4: Where ever the graph rises very steeply that volume is the equilibrium point of the titration curve.
Step-5: The pH is determined from the titration curve where the volume is ½ the volume at equilibrium point.
This method will be sufficient for determining the pKa of a monoprotic acid, but in case of polyprotic acid the
dpH
equilibrium points may not be sharp so in that case the is plotted against V (volume of NaOH solution added).
dV
This first order derivative gives sharp points of equilibrium. From those peaks the equilibrium volumes are determined
V1 V1+ V 2 V 2 +V 3
(say V1, V2, V3 etc). pKa1 = pH at , pKa2 =pH at and pKa3 = .
2 2 2
pH pH
pKa2
pKa
V1/2 V1
Volume of NaOH soln.
Fig. Titration curve of a monoprotic acid pKa1
V1 V2
1 1
V1 (V1+V2)
2 2
Fig. Titration curve of a diprotic acid
BPUT / M.Pharm. Sem-1 / Chapter-1 / Preformulation Studies / A. Samanta 6
Spectrophotometric method
Whenever a weak acid (HA) is dissolved in water some molecules will be ionized into H+ and A–. If the moiety A
absorbs UV or visible light then there will be two light absorbing species. Each species will have separate mola
absorptivity ( .)
Step-1: Determination of molar absorptivity of HA ( 1).
If solution of HA is prepared in HCl acid then all the molecules will remain in unionized (HA) state. So the
absorbance this solution will be only due to HA species: A1 = 1 b CT. where CT is the total concentration of
the drug n the solution. Where b is the pathlength of the cuvette.
Step-: Determination of molar absorptivity of A– ( 2).
If solution of HA is prepared in NaOH solution then all the molecules will remain in ionized (A–) state. So the
absorbance this solution will be only due to A– species: A2 = 2 b CT. where CT is the total concentration of the
drug in the solution.
Step-3: Determination of absorbance of a solution at any pH in between 2 to 11.
If the solution of the drug is prepared in a pH in between 2 to 11 then the solution will contain both HA and A–
ions but the concentration of each ion may vary. So the absorbance will be contribution of both HA and A–.
Therefore, A = 1 b C1 + 2 b C2 where C1 and C2 are the concentrations of HA and A– respectively in the solution.
Now equations are solved:
A = 1 b C1 + 2 b C2
and CT = C1 + C2.
Solving these two equations the values of C1 and C2 are obtained.
A 1 bC T bC A
C1 = and C2 = 2 T
1b 2b 1b 2b
N.B. In case of polyprotic acid the number of equations required will be more. For example for a triprotic acid (H3A)
there will be four species: H3A, H2A–, HA2–, and A3–. In this case eight simultaneous equations will be required to
determine the four unknown concentrations (C1, C2, C3 and C4) and four molar absorptivities ( 1, 2, 3, and 4)
A1 = 1 b C1 + 2 b C2 + 3 b C3 + 4 b C4 determined at 1. Eqn. 1
A2 = 1 b C1 + 2 b C2 + 3 b C3 + 4 b C4 determined at 2. Eqn. 2
… ….. ……. ….. ….. …..
A8 = 1 b C1 + 2 b C2 + 3 b C3 + 4 b C4 determined at 8. Eqn. 8
Now these eight equations may be solved by some computer program and the concentration terms are determined.
Putting those terms in each Handerson-Hasselbach equation for two conjugate species the pKa1, pKa2 and pKa3 can
be determined.
Solubility method
S S0
pH = pKa + log
S0
Where S = solubility of a drug at any pH and
S0 = intrinsic solubility of the drug, i.e. solubility of only the unionized form of the drug.
Step-I: Solubility of the drug is determined at a pH where all the molecules of the drug will remain in
unionized state (S0).
Step-: The pH is changed by 1 unit and the solubilities are determined (S).
(S S 0 )
Step-3: pH vs. log is plotted and the slope determined will give the Ka after necessary calculation.
S0
BPUT / M.Pharm. Sem-1 / Chapter-1 / Preformulation Studies / A. Samanta 7
Significance of pKa
1. From the pKa of a weak acid or weak base the unionized fraction of a drug can be determined at a certain pH. The
unionized fraction has greater absorption rate through any biological membrane. So while designing a dosage form
how a weak acid or weak base will behave in any biological fluid and its rate of absorption and the site of
absorption can be guessed from the pKa. From the table below it is evident that Ibuprofen, a weak acid is absorbed
maximum from stomach and Nitrazepam, a weak base will be absorbed preferrentially from duodenum.
Weak base
e.g. Nitrazepam [B] = 100 [B] = 100 [B] = 100
pKa = 3.2 of its
conjugate acid
[BH +] = 5012 [BH +] = 0.006 [BH +] = 1.6
2. The solubility of a weakly acidic and weakly basic drug can be increased if the drug remains in ionized state. So
the solubility vs. pH is plotted to get pH-solubility profile of a drug. While designing a dosage form (oral,
ophthalmic or parenteral) the pH the solution is buffered to that pH where the solubility is maximum and the drug
is reasonably stable.
SOLUBILITY
Definition
The maximum amount of solute that is soluble in one part of solution to make a saturated solution at a certasin
temperature is called the solubility of the drug.
Significance of solubility
1. Increased bioavailability:
• In dealing with a new drug substance, it is extremely important to know something about its solubility
characteristics, especially in aqueous solution, in order to elicit a therapeutic response. Any drug having
solubility less than 10mg/mL in physiologic pH range (pH 1 to 7) will produce bioabsorption problem. A
solubility less than 1mg/mL require salt formation of the drug for better bioavailability.
• When the solubility of a drug cannot be increased by salt formation (e.g. in neutral molecules, glycosides,
alcohols, steroids or where the pKa of a basic drug is less than 3 and the pKa of an acidic drug is more than
10) then the drug is dissolved with a cosolvent and filled in a soft gelatin capsule.
• Griseofulvin, an antifungal drug, when given orally the absorption is very less. So it is given with fat meal.
The rate of dissolution rate of griseofulvin is increased by micronization (in a fluid energy mill) or by solid
dispersion technique to increase its oral bioavailability.
2. Taste masking: Chloramphenicol is very bitter in taste so it is very difficult to make a paediatric liquid dosage form
with chloramphenicol base. Chloramphenicol palmitate is taken, the solubility of which is very low compared to
chloramphenicol base. When a suspension is prepared due to its low solubility it does not produce any bitter taste.
3. Reducing degradation in the GIT: Drugs like erythromycin will degrade while passing through the acid
environment of stomach, so erythromycin is delivered as erythromycin proprionate or estolate while preparing
paediatric suspension. This solubility of these esters are very less in acidic pH. Thus they are saved from gastric
pH.
BPUT / M.Pharm. Sem-1 / Chapter-1 / Preformulation Studies / A. Samanta 8
In case of weak acid and weak base the solubility can be manipulated by changing the pH of the solution.
In case of non-ionizable molecules the solubility can be manipulated either by changing the solvent, or by addition of
cosolvent or by complexation.
• In case of assaying a drug by chromatography or spectrophotometry any solvent in which the drug is adequately
soluble may be taken. For example aqueous methanol for HPLC, chloroform in spectrophotometry, etc.
HP solid HP sol
HP sol + H20 H3O+ + P
Since the concentration of the unionized form in solution [HP]sol is constant, so S0 = [HP]sol and the constant for acid-
[H O + ][P ] [ HP]
base equilibrium, equation is: K a = 3 or, [ P ] = K a
[ HP ] [H 3O + ]
The total solubility S of phenobarbital will be:
S0 Ka
S = [HP] + [P–] or, S = S 0 + K a or, S = S0 1+
[ H 3O ]+
[H 3O + ]
BPUT / M.Pharm. Sem-1 / Chapter-1 / Preformulation Studies / A. Samanta 10
PARTITION COEFFICIENT
If a drug is added to the immiscible solvents, the drug will be distributed between two layers. At equilibrium the ratio
of concetration of drug in two layers will be constant.
C
K= 1 where C1 = concentration of drug in liquid-1.
C2
C2 = concentration of drug in liquid-2.
K = distribution coefficient
The equilibrium constant K is known as the distribution ratio, distribution coefficient, or partition coefficient.
N.B. This equation is true when the solution is a dilute one. In concentrated solution the activity should be determined.
a C
i.e. K = 1 = 1 1
a2 2C 2
Co [ HA] O + [( HA) n ] O
K' = =
CW [ HA]W + [ A ]W
2. Extraction
To determine the efficiency with which one solvent can extract a compound from a second solvent the value of K is
required in both solvents. This extraction principle is required in
• analytical chemistry to develop the solvent system of TLC, HPLC and HPTLC
• in synthetic chemistry to purify a drug and
• in separating the active constituents from crude drug extract of plants or animals.
BPUT / M.Pharm. Sem-1 / Chapter-1 / Preformulation Studies / A. Samanta 11
In case of extraction of a costly drug from its crude drug e.g. vincristine or vinblastine from Vinca rosea the minimum
number of extraction steps (n) is large.
In case of a low cost drug if the number of extraction steps are large then additional cost due to each extraction step
(like the cost of solvent, energy or manpower) will increase which will make the process uneconomical. So by
determining the partitioning effect (K) in the two solvents and from the above equations the minimum theoretical
number of extraction steps are calculated.
Enzymes produced by yeasts, molds and bacteria must be destroyed or inhibited to prevent deterioration of product.
Example: Sodium benzoate is frequently used as preservative, especially in food and oral products. The preservative
action of sodium benzoate is due to unionized benzoic acid only.
The MIC90 of benzoic acid = 25 mg/100ml.
This is probably due to greater penetration of unionized acid (HA) through the biological membranes of
microorganisms.
Microorganisms generally resides in aqueous phase and oil-water interface. So the concentration of [HA] > MIC90 of
the benzoic acid. Benzoic acid will be distributed into oil and water phases. So for determining the preservative
concentration of sodium benzoate calculations must be carried out to keep [HA] > MIC90 in the aqueous phase.
The partition coefficient of a drug is an indication of the lipophilic and hydrophilic character of a drug molecule.
For example a lipophilic sedative drug can cross the blood-brain-barrier quickly and thus it will produce quick onset of
action. But a very lipophilic drug is difficult to be carried from the site of absorption, through blood (aqueous), to brain.
So the molecule must have optimum hydrophilicity also so that it can be carried by the aqueous blood.
During preformulation studies partition coefficients in various oil phases correlates well with the permeation of various
biological membranes.
Example:
Oil phase Biological membrane
n-butanol Buccal
n-pentanol
n-octanol
Ethyl acetate Gastrointestinal
Ether
Oleyl alcohol
Toluene
Cyclohexane Blood brain barrier
Heptane
Carbontetrachloride
BPUT / M.Pharm. Sem-1 / Chapter-1 / Preformulation Studies / A. Samanta 12
Crystal Habit
Crystals may have different external structures (outer appearance) with a single internal structure. This external
structures are known as crystal habits.
Crystal habits are influenced by the environment of the growing crystals. Five types of crystal habits are generally
recognized during crystallization.
(i) Platy: plates, crystal growth in length and width and moderate height.
(ii) Acicular: needle-like, crystal growth in one direction.
(iii) Tabular: moderate expansion of two parallel faces.
(iv) Bladed: flat acicular
(v) Prismatic: columns.
Polymorphism
When crystals exists in more than one internal structure (i.e. packing pattern) the various crystalline forms are called
polymorphs and the phenomenon is known as polymorphism.
Depending on the thermodynamic stability, the polymorphs are divided into three categories stable, metastable and
unstable.
Unstable form has a tendency to transform into stable form. Metastable forms in dry state will remain stable, but if
melted or dissolved will form stable polymorph.
Characteristics of polymorphs
Example: Chloramphenicol palmitate has three polymorphs (stable), (metastable) and (unstable). When
chloramphenicol palmitate suspension is prepared from or polymorph it is found that bioavailabilty is higher with
the metastable form.
Example: Two polymorphs of aspirin can be obtained by recrystallization of aspirin from 95% ethanol or n-hexane. The
polymorph obtained from n-hexane is found to have greater solubility in water than the polymorph obtained from
ethanol.
BPUT / M.Pharm. Sem-1 / Chapter-1 / Preformulation Studies / A. Samanta 13
Theobroma oil or cocoa butter suppositories are meant to be melted at body temperature 370C but should remain as
solid at room temperature during storage period.
Cocoa butter is available in three polymorphs– (m.p. 200C), (m.p.360C) and (m.p. 150C). -form is the metastable
form, -form is the stable form and -form is the unstable form. During melting of cocoa butter by fusion method the
following phenomena are found:
So during preparation of cocoa butter suppositories 2/3rd portion of cocoa-butter base is melted and then the container is
removed from the heat source. The rest of the base is melted by stirring only without application of heat.
In case of a suspension the particles will sediment below and the particles will come closer to each other. During a long
storage life the suspension may experience several cycles of temperature change. During the hot period the metastable
form will get dissolved in the stagnant layer and during the cool period the particles will grow and crystal bridges may
form with the stable crystals. These crystal-bridges will give rise to irreversible caking of suspension.
Amorphous form
If a solid does not have any fixed internal structure that form is called amorphous form. They have molecules randomly
placed as in a liquid. E.g. Amorphous novobiocin.
Characteristics of amorphous forms:
Melting point: Stable > metastable form > unstable form > amorphous form of the same drug
Dissolution rate: Stable < metastable form < unstable form < amorphous form of the same drug
Preparation
Amorphous forms are prepared by rapid precipitation, lyophillization or rapid cooling of molten liquids e.g. glass
Polymeric materials
Polymers are very large molecules. They are so large and flexible that it is not possible for them to align perfectly to
form crystals. They usually have ordered regions within the structure, surrounded by disorder, so they are described as
semicrystalline. The degree of crystallinity depends up on processing conditions.
Molecular Adducts
During the process of crystallization, some compounds have a tendency to trap the solvent molecules.
This molecular complex has incorporated the crystallizing solvent molecules into specific sites within the crystal lattice
and has stoichiometric number of solvent molecules complexed.
When the incorporated solvent is water, the complex is called hydrates and when the solvent is other than water, the
complex is called solvates. Depending on the ratio of water molecules within a complex the following nomenclature is
followed.
(i) Anhydrous : 1 mole compound + 0 mole water
(ii) Hemihydrate: 1 mole compound + ½ mole water
(iii) Monohydrate: 1 mole compound + 1 mole water
(iv) Dihydrate : 1 mole compound + 2 moles water
FLOW RATE
1. Powders are required to produce tablets or capsules. Free flowing powders flow uniformly into the die cavity of
tablet punching machine and inside the empty gelatin shells. A free flowing powder produces uniform content of
drug in the tablets and capsules.
2. Free flowing powders show reproducible filling of tablet dies and capsules dosators, which improve weight
uniformity and physicomechanical properties (e.g. hardness).
3. Poor powder flow can result in excess entrapped air within powders which in some high-speed tabletting
conditions may promote capping or laminations.
4. Poor powder flow can result from excess fine particles in a powder, which increase friction in between particle and
die wall. It may cause lubrication problem.
5. In industry powders are required to flow from one location to another and this is achieved by different methods,
such as gravity feeding, fluidization in gases and liquids and hydraulic transefer. In each of these examples
powders are required to flow.
6. In capsule filling machine, especially Lily type capsule filling machine the powder must be free flowing to
uniformly fill the base of the capsule shells. In case of Zanasi-type filling machine cohesive powders are required.
Angle of repose
d
Tilting table Angle of repose
Observations
Same powder may produce different angle of repose due to
(a) different methods of determination
(b) different ways the samples were handled prior to measurement.
Interpretation
As a general guide > 500 unsatisfactory powder flow
< 250 very good powder flow
250 < < 500 satisfactory flow
Observations
It is found that if is increased then also increases. Generally the plot of versus is called Mohr diagram.
normal force
Normal stress ( ) =
cross sec tional area of powder Normal
normal shear force stress
Shear stress ( ) =
cross sec tional area of powder te
Mohr diagram
Slope = tan = coefficient of friction a Shear
= angle of internal friction stress
a = apparent tensile strength
Fig. Mohr diagram
te = cohesion coefficient.
Direct methods
Recording flow-meter
Powder flows from a hopper on to a balance. In analogue balance a chart Fig. 13
recorder is used to produce a permanent record of increase in powder mass
with time. In digital balance the flow rate is measured with time.
g/sec
Remedy:
• Granules are prepared for making coarse particles. Granules are Digital Balance
prepared for making coarse particles.
• Granules are sieved to get particles of uniform size distribution.
• During lubrication the granules are mixed gently to reduce the fines.
BPUT / M.Pharm. Sem-1 / Chapter-1 / Preformulation Studies / A. Samanta 18
Texture
Very rough surface more cohesive interlocking.
Smooth surface particles less cohesive good flow
Remedies:
(i) Acicular particles can be made spherical by temperature-cycling crystallization.
(ii) Spray-drying produces near spherical particles.
(iii) Solvent is sprayed on a bed of coarse particles while the granules are rotated inside a pan-coater. The sharp
edges will be smoothed or rounded.
(iv) Texture may be altered by controlling the production method, for example crystallization condition.
Moisture content
Adsorbed surface moisture films tends to increase bulk density and reduce porosity.
Remedies:
1. If excessive moisture content is present the powder is dried (up to 4% moisture content).
2. If the powder has hygroscopicity then it is stored and processed in low-humidity conditions.
3. If the powder is excessively dried then static charge will develop on the powder particles in that case moisture is
sprayed and mixed gently.