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1. I.INTRODUCTION
1.Asthama
• Asthma is a chronic inflammatory disorder of the airways in which many
cells and cellular elements play a role. The chronic inflammation is
associated with airway hyper responsiveness that leads to recurrent
episodes of wheezing, breathlessness, chest tightness and coughing,
particularly at night or in the early morning.
1.1. Asthma Therapy
1.1.1) Short acting B2 adrenergic agonist /quick-relief medications /relievers.
– Ex- Salbutamol,Terbutaline,Pirbuterol.
1.1.2) Long acting B2 adrenergic agonist /controllers.
– Ex- Salmeterol, Formoterol.
1.1.3) Inhaled Corticosteroid.
– Ex- Momentasone Furoate, Fluticasone Propionate.
2. 1.2. Devices used in Inhalation therapy.
Nasal Spray.
Pressurized metered dose inhaler.(pMDI)
Dry powder inhaler.(DPI)
1.2.1. Advantages of DPI over pMDI and Nasal Spray.
Minimal extra –pulmonary loss of drug due to low Oropharyngeal
deposition, low device retention and low exhaled loss.
Better patient compliance, simple to use and convenient to carry and do
not require spacers.
Stability is more as compared to MDI as the formulation is present in dry
state.
Breath actuated hence no hand-mouth coordination is required
3. 1.3.Types of Dry Powder Inhaler
1.3.1) Unit Dose Devices .
Ex- Spinhaler, Rotahaler, Lupihaler
1.3.2) Multiunit Dose DPI.
a) Device metered DPI. Ex- Turbohaler
b)Pre-metered DPI Devices. Ex- Advair diskus
1.3.3) Active Devices . Ex- Exubera.
Figure 1. Mechanism of deposition
4. 1.4. Capsules used in DPI
1.4.1. Qualicaps –I Gelatin capsules :
Capsules have been made from Gelatin. These are inhalation grade of gelatin
capsules designed to give good powder emptying properties.
1.4.2. Qualicaps –I PEG/Gelatin capsules :
Capsules with 5 % polyethylene glycol 4000 for inhalation have improved
puncturing properties when compared to gelatin capsules because of
plasticizing effect of polyethylene glycol. When exposed to low humidity
conditions Qualicaps –I PEG/gelatin capsules are less brittle as compared to
standard gelatin capsules.
1.4.3. Qualicaps –VI capsules :
Hypromellose capsules made from materials of plant origin and have the
following characteristics,
1) Lower moisture content.
2) Less potential for static charging.
3) Good cutting and puncturing performance.
4) Less particles shed from capsule wall.
5. 1.5. Carriers used in DPI
Lactose
Mannitol
Trehalose
Sorbitol
1.5.1. Key Parameters of Carrier particles used in preparation of DPI
Particle Size Distribution.
Surface area.
Surface energy.
Particle Shape.
Particle roughness.
Static charge
6. 2.REVIEW OF LITERATURE
• Hamid et.al has reported that the drug deposition is mainly controlled by
the Aerodynamic diameter. Particles larger than 5 micron are mostly
trapped by Oropharyngeal deposition and incapable of reaching the lungs
while smaller than 1 micron are exhaled without the deposition.
• Apte Shirish Prakash has reported that the adhesive force between the
drug and carrier particles must be weak enough so that the drug particles
can be released from excipient particles upon Aerosolisation to form an
acceptable FPF. He has concluded that at drug to carrier ratio 1:5 and 1:85
found greatest FPF at a ratio of 1:10,and a minimum surface energy
interaction between drug and carrier particles was necessary to separate
the highly cohesive, micronized drug particles during the inhalation.
• Young et.al observed the linear relationship between fine particle fraction
(FPF) and the fine lactose content when the fine lactose content was
below 15 % with both freshly milled and recrystallized samples showing
the similar trends.
7. • Martin et.al have explained that the effect of carrier particle size and surface
roughness on the aerosol performance of Dry powder inhaler formulations.
They have explained the lactose carriers of two grades,1)Anhydrous lactose 2)
Granular lactose. Anhydrous carriers exhibited minimal surface roughness and
behaves generally as smaller carriers have more performance as compared to
larger carriers while in case of granular carriers have high degree of surface
roughness and the dispersion performance of larger carriers exceeded that of
smaller size fractions.
• Martin Jan Telko has reported that most DPI formulations consist of
micronized drug blended with larger carrier particles. The interactions
between drug and carrier are the major determinant of DPI performance.
Electrostatic interactions between particles are recognized as a one mode of
particle interaction and the in vitro and in vivo study indicated that the
electrostatic charge affects the delivery and deposition of aerosol particles in
the lung.
8. 3. AIM AND OBJECTIVE
To study the effect of Micromeritic properties and Static charge on the
performance of dry powder inhaler.
Objectives of this present study are ;
Physical characterization of Drug and Excipient particles for Particle size
distribution, Morphology, Surface area, Surface energy, and Static charge.
Drug-Excipient Compatibility study.
Formulation of various batches of Drug – Carrier blend. and filling of Blend
in to the capsules.
Evaluation of Dry powder inhaler.
Explanation about the effect of Micromeritic properties and Static Charge
on the performance of Dry Powder Inhaler.
9. 4.SCOPE AND PLAN OF WORK
Literature
review
Selection of
drug &
excipient
Characterization
of APIs and
excipient
Designing and
preparation dry powder
inhaler with different
grade of lactose
Evaluation of
prepared
formulation
Stability study of
optimized formulation
10. 5.DRUG AND EXCIPIENT PROFILE
5.1. Long acting beta2 agonist (LABA)
– Pharmacopoeial status: IP
– Description: A white to off white powder.
– Category: Adrenergic beta2 agonist, Bronchodilator.
– Half life: 5.5 hrs
– Protein binding: 96%
– Increased cAMP levels cause relaxation of bronchial smooth muscle
and inhibit the release of pro-inflammatory mast-cell mediators such
as histamine and leukotrienes.
5.2. Inhaled corticosteroids (ICS)
– Pharmacopoeial status: IP
– Description: A white or almost white powder.
– Category: Anti-inflammatory, Anti-allergic, Bronchodilator agent.
– Half life: 7.8 hrs
– Protein binding: 91%
– The anti-inflammatory actions of corticosteroids involve inhibition of
cytosolic phospholipase A2 (through activation of lipocortin-1
(annexin)) which controls the biosynthesis of potent mediators of
inflammation such as prostaglandins and leukotrienes.
11. 5.3. Excipient profile
• Lactose monohydrate (USP/NF)
– Description: Lactose appears as various isomeric forms, α-lactose
monohydrate, α-lactose anhydrous, and β-lactose anhydrous. The stable
crystalline forms of lactose are α-lactose monohydrate, β-lactose
anhydrous and stable α -lactose anhydrous.
– Lactose occurs as white to off-white crystalline particles or powder.
Lactose is odourless and slightly sweet-tasting; α -lactose is approximately
20% as sweet as sucrose, while β -lactose is 40% as sweet.
– Category: Dry powder inhaler carrier; lyophilisation aid; tablet binder;
tablet and capsule diluents; tablet and capsule filler.
– Chemical formula : C12H22O11.H2O
– Molecular weight: 360.31
– Melting point: 201–2020 C
– Solubility: Practically insoluble in Chloroform, Ethanol, Ether and freely
soluble in water.
13. 7. METHODS USED FOR CHARACTERISATION
1)Particle Size Analysis of API & CARRIER particles by laser light diffraction
method.
2)Determination of Particle morphology of API & CARRIER particles by
Morphology G3-ID.
3)Particle surface area by Nitrogen adsorption method.
4)Surface energy by inverse-gas chromatography.
5)Static charge on drug particles and carrier by The JCI Faraday pail.
14. 7.1. CHARACTERISATION BY XRD & FT-IR
The X-ray powder diffraction study was performed to know the
crystallinity of the APIs. The spectra were recorded using shimadzu
superior TD 3000 X-ray diffractometer. The samples were run at regular
scan with 0-50 degree 2 theta range and step size was 0.01deg.
FT-IR was performed to know the compatibility of APIs and lactose
carriers. The spectra were recorded using FTIR Bruker Alpha. The scanning
range was 400-4000 cm-1 and the resolution was 2 cm-1.
18. 9. EVALUATION OF PREPARED DRY POWDER INHALER
Physical appearance.
Flow property of each formulation.
Determination of particle size distribution.
Determination of particle morphology of prepared formulations.
Determination of specific surface area prepared formulations.
Total surface energy of prepared formulations.
Average net content.
Uniformity of Weight.
Uniformity of drug content.
Uniformity of the Delivered Dose.
Assay.
Determination of fine particle fraction by ACI.
Stability study of optimized batch.
19. 10. STABILITY STUDY
The formulation F6 was optimized as it showed the highest respirable
fraction i.e. % Fine Particle Fraction (%FPF) of all the formulations (F1-F7).
The formulation were packed in HDPE 30 cc container and sealed and
studies were carried out for 90 days by keeping at 40 + 2oC and 75 + 5%
RH.
A drug formulation is said to be stable if it fulfills the following
requirements:
It contains at least 90% of the stated active ingredient.
It does not exhibit softening of the capsules.
It does not exhibit discoloration of the blend.
It does not exhibit any brittleness of the capsules when operated in
the device.
20. 11. RESULTS
I. Characterization of drugs : LABA
Sl. No. Test Observation IP Specification
1 Description Off white powder A white to off white powder
2 Solubility Complies
Sparingly soluble in water, freely soluble in
methanol, slightly soluble in ethanol
3 Identification Complies
IR spectrum of the sample should exhibit
absorption maxima and minima at the same
wavelength as that of IR spectra of similar
preparation of LABA standard.
4 Moisture content 0.026 % 0.5 %
5 Melting point 76 0C 75.5-76.5 0C
6 Assay 100.6 % 97-102 %
21. ICS
• ICS
Sl. No. Test Observation IP Specification
1 Description A white powder A white or almost white powder
2 Solubility Complies
Practically insoluble in water, slightly soluble in methanol
& ethanol, freely soluble in dimethyl sulfoxide.
3
Identificatio
n
Complies
IR spectrum of the sample should exhibit absorption
maxima and minima at the same wavelength as that of IR
spectra of similar preparation of ICS standard.
4
Moisture
content
0.147 % 0.5 %
5
Melting
point
272.6 0C 272-273 0C
6 Assay 98.9 % 96-102 %
22. II. Particle size distribution of drugs
Sr.no API D 10 D 50 D 90
1 ICS 1.85 micron 2.94 micron 3.46 micron
2 LABA 2.4 micron 3.26 micron 3.94 micron
API Specific surface area m2/gm Surface energy mJ/gm
ICS 6.75 54
LAB
A
5.98 47
III. Specific Surface area and Surface energy of Drugs
23. IV. Characterization of Excipients
I) Particle size distribution of Lactose monohydrate
Sr.no Lactose grade D 10 D 50 D 90
1 Lactohale 200 10.23 micron 75.46 micron 140.70 micron
2 Lactohale 230 4.53 micron 34.56 micron 55.78 micron
3 Lactohale 300 2.56 micron 4.58 micron 9.89 micron
Sr.no API Specific surface area m2/gm Surface energy mJ/gm
1 Lactohale 200 0.342 40.25
2 Lactohale 230 0.758 42.63
3 Lactohale 300 1.80 45.85
II) Specific Surface area and Surface energy measurements
25. 12. EVALUATION OF PREPARED DRY POWDER INHALER
I. Flow property
Material Bulk density
(gm/ml)
Tapped density
(gm/ml)
Hausner’s ratio
F1 0.687 0.935 1.360
F2 0.672 0.998 1.485
F3 0.632 1.056 1.670
F4 0.613 1.042 1.699
F5 0.597 1.048 1.755
F6 0.587 1.020 1.737
F7 0.561 1.024 1.825
26. II. Particle size distribution of the prepared formulation.
Material D10(μm) D50(μm) D90(μm)
F1 9.84 68.98 138.69
F2 9.65 67.09 136.67
F3 9.59 66.89 132.39
F4 9.02 64.05 129.37
F5 8.96 63.96 124.56
F6 8.54 53.43 108.98
F7 7.85 51.25 93.45
27. III. Determination of Surface Area and Energy
Formulations Specific surface area (m2/g) Surface energy (mJ/gm)
F1 0.61 40.55
F2 0.65 40.67
F3 0.70 40.87
F4 0.72 40.96
F5 0.78 42.38
F6 0.92 42.95
F7 1.024 44.87
28. IV. Average net content
Sr.no Formulation Average net content
1 F1 22.60
2 F2 22.78
3 F3 22.96
4 F4 23.65
5 F5 23.75
6 F6 24.66
7 F7 25.07
29. V. Uniformity of Drug Content
Batches % LABA % ICS
F 1 99.21 100.84
F 2 99.26 103.19
F 3 98.85 102.09
F 4 101.61 101.41
F 5 103.2 99.81
F6 102.15 99.18
F7 102.44 98.89
30. VI. Assay
Formulation % LABA %ICS
F1 97.5 96.4
F2 98.7 95.7
F3 99.4 94.3
F4 93.3 92.7
F5 96.8 91.8
F6 101.2 95.9
F7 100.6 93.2
31. VII. Uniformity of Delivered Dose.
Batches % ICS % LABA
F1 81.8 81.66
F2 86.3 82.3
F3 93.38 90.8
F4 87.8 90.4
F5 90.3 83.2
F6 89.4 86.4
F7 91.6 87.3
36. XI. Effect of Static Charge on the Performance of Dry Powder
Inhaler
Blend
Static charge
(nC/gm)
E.D
(in %)
F.P.F
(ICS)
F.P.F
(LABA)
F1 0.27 63.59 14.64 29.29
F2 0.31 64.55 15.53 30.03
F3 0.35 63.25 15.74 30.13
F4 0.37 68.93 18.24 30.58
F5 0.46 62.45 21.44 30.92
F6 0.54 68.47 24.43 33.12
F7 0.60 65.75 21.54 29.21
37. XII. Physical Observation After Doing Stability Study
Initial 1 Month 2 Month 3 Month
No sticking of blend inside
the capsule shell, No
softening of the capsules.
No colour change of the
blend
No sticking of blend inside
the capsule shell, No
softening of the capsules.
No colour change of the
blend
Very less sticking of blend
inside the capsule shell,
No softening of the
capsules. No colour
change of the blend
Less sticking of blend
inside the capsule shell,
No softening of the
capsules. No colour
change of the blend
Sr.no Batch F.P.F Initial F.P.F (1 M) F.P.F (2 M) F.P.F (3 M)
1 F1 14.64 14.58 14.34 14.08
2 F2 15.53 15.34 15.18 14.92
3 F3 15.74 15.64 15.36 15.12
4 F4 18.24 18.15 17.64 17.45
5 F5 21.44 21.36 21.18 20.98
6 F6 24.43 24.32 24.09 23.87
7 F7 21.54 21.24 21.02 20.89
In-Vitro Deposition of ICS
38. In-Vitro Deposition of LABA
Sr.no Batch F.P.F(Initial) F.P.F (1 M) F.P.F(2 M) F.P.F (3 M)
1 F1 29.29 29.04 28.56 28.12
2 F2 30.03 29.91 29.64 29.03
3 F3 30.13 30.02 29.85 29.12
4 F4 30.58 30.22 29.59 29.04
5 F5 30.92 30.54 29.45 29.07
6 F6 33.12 31.98 31.45 31.02
7 F7 29.21 28.98 28.35 27.79
39. 13.DISCUSSION
The Drugs & Excipients were analysed for different parameter and they
were found within the required specification limits.
LABA & ICS sample with a particle size d90 smaller than 5 μm exhibited
a suitable particle size range for DPI formulation.
X-ray diffraction indicating no change in the crystallinity of the APIs and
excipient in the formulation.
Physical appearance of all the formulation was good.
Flow property depend on the ratio of fine lactose and coarse lactose.
From the morphology study it was found that there are some roughness or
crevices present on the surface of carrier particle which is essential for
aggregation of drug particle on the surface of carrier particle.
40. The specific surface area was found within the range of 0.61-0.79 m2/g.
The highest surface area was found for the formulation F9 was due to the
presence of LH 300 which has very small particle size. Thus specific surface
area depends on the particle size of lactose monohydrate.
The average net content of all the formulations was within the limit that is
between 22.5-27.5 mg.
The percentage of drug content per capsule in all the formulations was
found to be within the limit of 85-115%.
From the results the delivered dose for all the formulations comply within
the limits as all the results lie between 75% and 125% of the assay value.
The assay result of all the formulations were within the limit of not less
than 90% and not more than 125%.
41. The average net content of all the formulations was within the limit
that is between 22.5-27.5 mg.
The percentage of drug content per capsule in all the formulations
was found to be within the limit of 85-115%.
From the results the delivered dose for all the formulations comply
within the limits as all the results lie between 75% and 125% of the
assay value.
The assay result of all the formulations were within the limit of not
less than 90% and not more than 125%.
42. The formulation F1 which do not contain fine grade lactose had shown respirable
fraction as low as compared to other formulations. The formulation F3 had shown
the highest respirable fraction, which may be due to the high energy surface of the
coarse lactose occupied by the fine lactose and the remaining surface occupied by
the drug which get easily separated from the coarse lactose under the inhalation
force. Further increase in the concentration of fine grade lactose in the formulation
F4 & F5, there was no significant change occurs in fine particle fraction indicating
that the active sites of coarse lactose was saturated with fine grade lactose. The
formulation F9 had shown the lowest respirable fraction as compared to
formulation F6, F7 and F8, which consists of Respitose SV003 as fine lactose.
Stability study complies .
43. 14. CONCLUSION
• Most drugs are sheltered within asperities on larger carriers and thus less
susceptible to detachment by flow stream, and thus resulting in decrease in
the fine particle fraction by increasing the particle size. Smaller carrier
particles possess smoother surfaces relative to larger carriers. Thus the carrier
particles which are smaller in size shows higher Fine Particle fraction as
compared to that of Larger carrier particles.
• Due to reduction in the carrier particle size the surface area of carrier particle
gets increased which causes the increase in the surface energy of the
formulation resulting in increase in the carrier – drug particle adhesion
resulting in increase in fine particle fraction of the drug particle.
• Based on the nature of carrier particle (Either crystalline or amorphous) the
performance of dry powder inhaler gets varied. The crystalline particles have
more number of sites of attachments as compared to that of amorphous
particles thus providing more number of sites of attachments to drug particles
to the carrier particles as compared to that of amorphous particles and
resulting in increase in fine particle fraction.
44. • Further increase in the amount of fine fraction of carrier particles results
in increase in surface energy and static charge o such an extent that the
dispersion of drug particles from the carrier particles becomes difficult
thus resulting in decrease in Fine Particle Fraction of Drug particle from
carrier particle.
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