2.9.18. PREPARATIONS FOR Code Item Description Dimen- sions* …library.njucm.edu.cn › yaodian ›...

EUROPEAN PHARMACOPOEIA 5.1 2.9.18. Preparations for inhalation

04/2005:20918

2.9.18. PREPARATIONS FORINHALATION: AERODYNAMICASSESSMENT OF FINE PARTICLESThis test is used to determine the fine particle characteristicsof the aerosol clouds generated by preparations forinhalation.

Unless otherwise justified and authorised, one of thefollowing apparatus and test procedures is used.

Stage mensuration is performed periodically together withconfirmation of other dimensions critical to the effectiveoperation of the impactor.

Re-entrainment (for apparatus D and E). To ensure efficientparticle capture, coat each plate with glycerol, silicone oilor similar high viscosity liquid, typically deposited froma volatile solvent. Plate coating must be part of methodvalidation and may be omitted where justified and authorised.

Mass balance. The total mass of the active substance is notless than 75 per cent and not more than 125 per cent ofthe average delivered dose determined during testing foruniformity of delivered dose. This is not a test of the inhalerbut it serves to ensure that the results are valid.

APPARATUS A - GLASS IMPINGER

The apparatus is shown in Figure 2.9.18.-1 (see alsoTable 2.9.18.-1).

Figure 2.9.18.-1. – Apparatus A: glass impinger

Dimensions in millimetres (tolerances ± 1 mm unlessotherwise prescribed)

Table 2.9.18.-1. – Component specification for apparatus Ain Figure 2.9.18.-1

Code Item Description Dimen-sions*

A Mouthpieceadaptor

Moulded rubber adapter for actuatormouthpiece.

B Throat Modified round-bottomed flask : 50 ml

— ground-glass inlet socket 29/32

— ground-glass outlet cone 24/29

C Neck Modified glass adapter :


— ground-glass outlet cone 24/29

Lower outlet section ofprecision-bore glass tubing :

— bore diameter 14

Selected bore light-wall glass tubing :

— external diameter 17

D Upper Modified round-bottomed flask 100 ml

impingement — ground-glass inlet socket 24/29

chamber — ground-glass outlet cone 24/29

E Coupling tube Medium-wall glass tubing :

— ground-glass cone 14/23

Bent section and upper verticalsection :


Lower vertical section :


F Screwthread, Plastic screw cap 28/13

side-arm Silicone rubber ring 28/11

adaptor PTFE washer 28/11

Glass screwthread :

— thread size 28

Side-arm outlet to vacuum pump:

— minimum bore diameter 5

G Lower jetassembly

Modified polypropylene filter holderconnected to lower vertical sectionof coupling tube by PTFE tubing.

seeFigure2.9.18.-1

Acetal circular disc with the centresof four jets arranged on a projectedcircle of diameter 5.3 mm with anintegral jet spacer peg : 10

— peg diameter 2

— peg protrusion 2

H Lower Conical flask 250 ml

impingementchamber


* Dimensions in millimetres, unless otherwise stated.

Procedure for nebulisersIntroduce 7 ml and 30 ml of a suitable solvent into the upperand lower impingement chambers, respectively.Connect all the component parts. Ensure that the assemblyis vertical and adequately supported and that the jet spacerpeg of the lower jet assembly just touches the bottom ofthe lower impingement chamber. Connect a suitable pumpfitted with a filter (of suitable pore size) to the outlet of theapparatus. Adjust the air flow through the apparatus, asmeasured at the inlet to the throat, to 60 ± 5 litres/min.

General Notices (1) apply to all monographs and other texts 2799

2.9.18. Preparations for inhalation EUROPEAN PHARMACOPOEIA 5.1

Introduce the liquid preparation for inhalation into thereservoir of the nebuliser. Fit the mouthpiece and connect itby means of an adapter to the device.

Switch on the pump of the apparatus and after 10 s switchon the nebuliser.

After 60 s, unless otherwise justified, switch off thenebuliser, wait for about 5 s and then switch off the pump ofthe apparatus. Dismantle the apparatus and wash the innersurface of the upper impingement chamber collecting thewashings in a volumetric flask. Wash the inner surface ofthe lower impingement chamber collecting the washings in asecond volumetric flask. Finally, wash the filter precedingthe pump and its connections to the lower impingementchamber and combine the washings with those obtainedfrom the lower impingement chamber. Determine theamount of active substance collected in each of the 2 flasks.Express the results for each of the 2 parts of the apparatusas a percentage of the total amount of active substance.

Procedure for pressurised inhalersPlace the actuator adapter in position at the end of the throatso that the mouthpiece end of the actuator, when insertedto a depth of about 10 mm, lines up along the horizontalaxis of the throat and the open end of the actuator, whichaccepts the pressurised container, is uppermost and in thesame vertical plane as the rest of the apparatus.

Introduce 7 ml and 30 ml of a suitable solvent into the upperand lower impingement chambers, respectively.

Connect all the component parts. Ensure that the assemblyis vertical and adequately supported and that the lowerjet-spacer peg of the lower jet assembly just touches thebottom of the lower impingement chamber. Connect asuitable pump to the outlet of the apparatus. Adjust the airflow through the apparatus, as measured at the inlet to thethroat, to 60 ± 5 litres/min.

Prime the metering valve by shaking for 5 s and dischargingonce to waste ; after not less than 5 s, shake and dischargeagain to waste. Repeat a further 3 times.

Shake for about 5 s, switch on the pump to the apparatusand locate the mouthpiece end of the actuator in the adapter,discharge once immediately. Remove the assembled inhalerfrom the adapter, shake for not less than 5 s, relocate themouthpiece end of the actuator in the adapter and dischargeagain. Repeat the discharge sequence. The number ofdischarges should be minimised and typically would notbe greater than 10. After the final discharge wait for notless than 5 s and then switch off the pump. Dismantle theapparatus.

Wash the inner surface of the inlet tube to the lowerimpingement chamber and its outer surface that projectsinto the chamber with a suitable solvent, collecting thewashings in the lower impingement chamber. Determinethe content of active substance in this solution. Calculatethe amount of active substance collected in the lowerimpingement chamber per discharge and express the resultsas a percentage of the dose stated on the label.

Procedure for powder inhalersIntroduce 7 ml and 30 ml of a suitable solvent into the upperand lower impingement chambers, respectively.

Connect all the component parts. Ensure that the assemblyis vertical and adequately supported and that the jet-spacerpeg of the lower jet assembly just touches the bottom of thelower impingement chamber. Without the inhaler in place,connect a suitable pump to the outlet of the apparatus.Adjust the air flow through the apparatus, as measured atthe inlet to the throat, to 60 ± 5 litres/min.

Prepare the inhaler for use and locate the mouthpiece inthe apparatus by means of a suitable adapter. Switch on thepump for 5 s. Switch off the pump and remove the inhaler.Repeat the discharge sequence. The number of dischargesshould be minimised and typically would not be greaterthan 10. Dismantle the apparatus.Wash the inner surface of the inlet tube to the lowerimpingement chamber and its outer surface that projectsinto the chamber with a suitable solvent, collecting thewashings in the lower impingement chamber. Determinethe content of active substance in this solution. Calculatethe amount of active substance collected in the lowerimpingement chamber per discharge and express the resultsas a percentage of the dose stated on the label.

Fine particle dose and particle sizedistribution

APPARATUS C - MULTI-STAGE LIQUID IMPINGER

Figure 2.9.18.-4. – Apparatus C: multi-stage liquid impingerThe multi-stage liquid impinger consists of impactionstages 1 (pre-separator), 2, 3 and 4 and an integral filterstage (stage 5), see Figures 2.9.18.-4/6. An impaction stagecomprises an upper horizontal metal partition wall (B)through which a metal inlet jet tube (A) with its impactionplate (D) is protruding. A glass cylinder (E) with samplingport (F) forms the vertical wall of the stage, and a lowerhorizontal metal partition wall (G) through which the

2800 See the information section on general monographs (cover pages)


Figure 2.9.18.-5. – Apparatus C: details of jet tube and impaction plate. Inserts show end of multi-jet tube U leading tostage 4. (Numbers and lowercase letters refer to Table 2.9.18.-3 and uppercase letters refer to Figure 2.9.18.-4).

tube (H) connects to the next lower stage. The tube intostage 4 (U) ends in a multi-jet arrangement. The impactionplate (D) is secured in a metal frame (J) which is fastenedby 2 wires (K) to a sleeve (L) secured on the jet tube. Thehorizontal face of the collection plate is perpendicular tothe axis of the jet tube and centrally aligned. The uppersurface of the impaction plate is slightly raised above theedge of the metal frame. A recess around the perimeterof the horizontal partition wall guides the position of theglass cylinder. The glass cylinders are sealed against thehorizontal partition walls with gaskets (M) and clampedtogether by 6 bolts (N). The sampling ports are sealed bystoppers. The bottom-side of the lower partition wall ofstage 4 has a concentrical protrusion fitted with a rubberO-ring (P) which seals against the edge of a filter placed inthe filter holder. The filter holder (R) is constructed as abasin with a concentrical recess in which a perforated filtersupport (S) is flush-fitted. The filter holder is dimensionedfor 76 mm diameter filters. The assembly of impaction stagesis clamped onto the filter holder by 2 snap-locks (T). Connectan induction port (see Figure 2.9.18.-7) onto the stage 1inlet jet tube of the impinger. A rubber O-ring on the jettube provides an airtight connection to the induction port. Asuitable mouthpiece adapter is used to provide an airtightseal between the inhaler and the induction port. The frontface of the inhaler mouthpiece must be flush with the frontface of the induction port.

Figure 2.9.18.-6. – Apparatus C: details of the filter stage(stage 5). Numbers refer to dimensions (Ø = diameter).

Uppercase letters refer to Table 2.9.18.-2.Dimensions in millimetres unless otherwise stated

Table 2.9.18.-2. – Component specification for apparatus Cin Figures 2.9.18.-4/6

Code* Item Description Dimen-sions**

A,H Jet tube Metal tube screwed onto partitionwall sealed by gasket (C), polishedinner surface

see Figure2.9.18.-5

B,G Partition wall Circular metal plate

— diameter 120

— thickness see Figure2.9.18.-5

C Gasket e.g. PTFE to fit jettube

D Impaction Porosity 0 sintered-glass disk

plate — diameter see Figure2.9.18.-5



Code* Item Description Dimen-sions**

E Glass cylinder Plane polished cut glass tube

— height, including gaskets 46

— outer diameter 100

— wall thickness 3.5

— sampling port (F) diameter 18

— stopper in sampling port ISO24/25

J Metal frame L-profiled circular frame with slit

— inner diameter to fitimpactionplate

— height 4

— thickness of horizontal section 0.5

— thickness of vertical section 2

K Wire Steel wire interconnecting metalframe and sleeve (2 for each frame)

— diameter 1

L Sleeve Metal sleeve secured on jet tubeby screw

— inner diameter to fit jettube

— height 6

— thickness 5

M Gasket e.g. silicone to fit glasscylinder

N Bolt Metal bolt with nut (6 pairs)

— length 205

— diameter 4

P O-ring Rubber O-ring

— diameter × thickness 66.34 × 2.62

Q O-ring Rubber O-ring

— diameter × thickness 29.1 × 1.6

R Filter holder Metal housing with stand andoutlet

see Figure2.9.18.-6

S Filter support Perforated sheet metal

— diameter 65

— hole diameter 3

— distance between holes(centre-points)

4

T Snap-locks

U Multi-jet tube Jet tube (H) ending in multi-jetarrangement.

see insertsFigure2.9.18.-5

* Refers to Figure 2.9.18.-4.** Measures in millimetres with tolerances according to iso 2768-munless otherwise stated.

Procedure for pressurised inhalers

Dispense 20 ml of a solvent, capable of dissolving theactive substance into each of stages 1 to 4 and replace thestoppers. Tilt the apparatus to wet the stoppers, therebyneutralising electrostatic charge. Place a suitable filtercapable of quantitatively collecting the active substancein stage 5 and assemble the apparatus. Place a suitablemouthpiece adapter in position at the end of the inductionport so that the mouthpiece end of the actuator, wheninserted, lines up along the horizontal axis of the inductionport and the inhaler is positioned in the same orientation as

intended for use. Connect a suitable vacuum pump to theoutlet of the apparatus and adjust the air flow through theapparatus, as measured at the inlet to the induction port, to30 litres/min (± 5 per cent). Switch off the pump.

Table 2.9.18.-3. – Dimensions(1) of jet tube with impactionplate of apparatus C

Type Code(2) Stage 1 Stage 2 Stage 3 Stage 4 Filter(stage 5)

Distance 1 9.5(-.0+.5)

5.5(-.0+.5)

4.0(-.0+.5)

6.0(-.0+.5)

n.a.

Distance 2 26 31 33 30.5 0

Distance 3 8 5 5 5 5

Distance 4 3 3 3 3 n.a.

Distance 5 0 3 3 3 3

Distance 6 (3) 20 25 25 25 25

Distance 7 n.a. n.a. n.a. 8.5 n.a.

Diameter c 25 14 8.0(± .1)

21 14

Diameter d 50 30 20 30 n.a.

Diameter e 27.9 16.5 10.5 23.9 n.a.

Diameter f 31.75(-.0+.5)

22 14 31 22

Diameter g 25.4 21 13 30 21

Diameter h n.a. n.a. n.a. 2.70(± .5)

n.a.

Diameter j n.a. n.a. n.a. 6.3 n.a.

Diameter k n.a. n.a. n.a. 12.6 n.a.

Radius(4) r 16 22 27 28.5 0

Radius s 46 46 46 46 n.a.

Radius t n.a. 50 50 50 50

Angle w 10° 53° 53° 53° 53°

Angle u n.a. n.a. n.a. 45° n.a.

Angle v n.a. n.a. n.a. 60° n.a.

(1) Measures in millimetres with tolerances according to ISO 2768-munless otherwise stated(2) Refer to Figure 2.9.18.-5(3) Including gasket(4) Relative centreline of stage compartmentn.a. = not applicable

Unless otherwise prescribed in the patient instructions,shake the inhaler for 5 s and discharge 1 delivery towaste. Switch on the pump to the apparatus, locate themouthpiece end of the actuator in the adapter and dischargethe inhaler into the apparatus, depressing the valve for asufficient time to ensure complete discharge. Wait for 5 sbefore removing the assembled inhaler from the adapter.Repeat the procedure. The number of discharges should beminimised and typically would not be greater than 10. Thenumber of discharges is sufficient to ensure an accurate andprecise determination of the fine particle dose. After thefinal discharge, wait for 5 s and then switch off the pump.

Dismantle the filter stage of the apparatus. Carefully removethe filter and extract the active substance into an aliquotof the solvent. Remove the induction port and mouthpieceadapter from the apparatus and extract the active substanceinto an aliquot of the solvent. If necessary, rinse the inside ofthe inlet jet tube to stage 1 with solvent, allowing the solventto flow into the stage. Extract the active substance from theinner walls and the collection plate of each of the 4 upper



Note

(1) Material may be aluminium, stainless steel or other suitable material.

(2) Machine from 38 mm bar stock.

(3) Bore 19 mm hole through bar.

(4) Cut tube to exact 45° as shown.

(5) The inner bores and tapers should be smooth — surface roughness Ra approx. 0.4 µm.

(6) Mill joining cads of stock to provide a liquid tight leak-free seal.

(7) Set up a holding fixture for aligning the inner 19 mm bore and for drilling and tapping M4 × 0.7 threads. There must be virtually nomismatch of the inner bores in the miter joint.

Figure 2.9.18.-7. – Induction port

Dimensions in millimetres unless otherwise stated

stages of the apparatus into the solution in the respectivestage by carefully tilting and rotating the apparatus,observing that no liquid transfer occurs between the stages.

Using a suitable method of analysis, determine the quantityof active substance contained in each of the aliquots ofsolvent.

Calculate the fine particle dose (see Calculations).

Procedure for powder inhalersPlace a suitable low resistance filter capable of quantitativelycollecting the active substance in stage 5 and assemble

the apparatus. Connect the apparatus to a flow systemaccording to the scheme specified in Figure 2.9.18.-8 andTable 2.9.18.-4. Unless otherwise defined, conduct the test atthe flow rate, Qout, used in the test for uniformity of delivereddose, drawing 4 litres of air from the mouthpiece of theinhaler and through the apparatus.



Figure 2.9.18.-8. – Experimental set-up for testing powderinhalers

Table 2.9.18.-4. – Component specification forFigure 2.9.18.-8

Code Item Description

A Connector ID ≥ 8 mm, e.g., short metal coupling, withlow-diameter branch to P3.

B Vacuumtubing

A length of suitable tubing having anID ≥ 8 mm and an internal volume of25 ± 5 ml.

C 2-way solenoidvalve

A 2-way, 2-port solenoid valve having aminimum airflow resistance orifice withID ≥ 8 mm and an opening time ≤ 100 ms.(e.g. type 256-A08, Bürkert GmbH,D-74653 Ingelfingen), or equivalent.

D Vacuum pump Pump must be capable of drawing therequired flow rate through the assembledapparatus with the powder inhaler in themouthpiece adapter (e.g. product type 1023,1423 or 2565, Gast Manufacturing Inc.,Benton Harbor, MI 49022), or equivalent.Connect the pump to the 2-way solenoidvalve using short and/or wide (ID ≥ 10 mm)vacuum tubing and connectors to minimisepump capacity requirements.

E Timer Timer capable to drive the 2-way solenoidvalve for the required duration (e.g. typeG814, RS Components International, Corby,NN17 9RS, UK), or equivalent.

P2P3

Pressuremeasurements

Determine under steady-state flow conditionwith an absolute pressure transducer.

F Flow controlvalve

Adjustable regulating valve with maximumCv ≥ 1, (e.g. type 8FV12LNSS, ParkerHannifin plc., Barnstaple, EX31 1NP, UK), orequivalent.

Connect a flowmeter to the induction port. Use a flowmetercalibrated for the volumetric flow leaving the meter, orcalculate the volumetric flow leaving the meter (Qout) usingthe ideal gas law. For a meter calibrated for the enteringvolumetric flow (Qin), use the following expression :

P0= atmospheric pressure,

∆P = pressure drop over the meter.

Adjust the flow control valve to achieve steady flow throughthe system at the required rate, Qout (± 5 per cent). Switchoff the pump. Ensure that critical flow occurs in the flowcontrol valve by the following procedure.

With the inhaler in place and the test flow rate established,measure the absolute pressure on both sides of the controlvalve (pressure reading points P2 and P3 in Figure 2.9.18.-8).A ratio P3/P2 of less than or equal to 0.5 indicates criticalflow. Switch to a more powerful pump and re-measure thetest flow rate if critical flow is not indicated.

Dispense 20 ml of a solvent, capable of dissolving the activesubstance into each of the 4 upper stages of the apparatusand replace the stoppers. Tilt the apparatus to wet thestoppers, thereby neutralising electrostatic charge. Place asuitable mouthpiece adapter in position at the end of theinduction port.

Prepare the powder inhaler for use according to patientinstructions. With the pump running and the 2-waysolenoid valve closed, locate the mouthpiece of the inhalerin the mouthpiece adapter. Discharge the powder intothe apparatus by opening the valve for the required time,T (± 5 per cent). Repeat the procedure. The number ofdischarges should be minimised and typically would not begreater than 10. The number of discharges is sufficient toensure an accurate and precise determination of fine particledose.

Dismantle the filter stage of the apparatus. Carefully removethe filter and extract the active substance into an aliquotof the solvent. Remove the induction port and mouthpieceadapter from the apparatus and extract the active substanceinto an aliquot of the solvent. If necessary, rinse the inside ofthe inlet jet tube to stage 1 with solvent, allowing the solventto flow into the stage. Extract the active substance from theinner walls and the collection plate of each of the 4 upperstages of the apparatus into the solution in the respectivestage by carefully tilting and rotating the apparatus,observing that no liquid transfer occurs between the stages.

Using a suitable method of analysis, determine the amount ofactive substance contained in each of the aliquots of solvent.


APPARATUS D - ANDERSEN CASCADE IMPACTOR

The Andersen 1 ACFM non-viable cascade impactorconsists of 8 stages together with a final filter. Material ofconstruction may be aluminium, stainless steel or othersuitable material. The stages are clamped together andsealed with O-rings. Critical dimensions applied by themanufacturer of apparatus D are provided in Table 2.9.18.-5.In use, some occlusions and weirs of pores will occur.In-use mensuration tolerances need to be justified. In theconfiguration used for pressurised inhalers (Figure 2.9.18.-9)the entry cone of the impactor is connected to an inductionport (see Figure 2.9.18.-7). A suitable mouthpiece adapteris used to provide an airtight seal between the inhaler andthe induction port. The front face of the inhaler mouthpiecemust be flush with the front face of the induction port.

In the configuration for powder inhalers, a pre-separatoris placed above the top stage to collect large masses ofnon-respirable powder. It is connected to the inductionport as shown in Figure 2.9.18.-10. To accommodate highflow rates through the impactor, the outlet nipple, used toconnect the impactor to the vacuum system is enlarged tohave an internal diameter of greater than or equal to 8 mm.



Table 2.9.18.-5. – Critical dimensions for apparatus D

Description Number Dimension (mm)

Stage 0 nozzle diameter 96 2.55 ± 0.025








Procedure for pressurised inhalersAssemble the Andersen impactor with a suitable filterin place. Ensure that the system is airtight. In thatrespect, follow the manufacturer’s instructions. Place asuitable mouthpiece adapter in position at the end of theinduction port so that the mouthpiece end of the actuator,when inserted, lines up along the horizontal axis of theinduction port and the inhaler unit is positioned in the sameorientation as the intended use. Connect a suitable pump tothe outlet of the apparatus and adjust the air flow throughthe apparatus, as measured at the inlet to the induction port,to 28.3 litres/min (± 5 per cent). Switch off the pump.Unless otherwise prescribed in the patient instructions,shake the inhaler for 5 s and discharge one delivery towaste. Switch on the pump to the apparatus, locate the

Figure 2.9.18.-9. – Apparatus D: Andersen cascade impactor used for pressurised inhalers



Figure 2.9.18.-10. – Connection of the induction port to the preseparator of the Andersen cascade impactorDimensions in millimetres unless otherwise stated

mouthpiece end of the actuator in the adapter and dischargethe inverted inhaler into the apparatus, depressing the valvefor a sufficient time to ensure complete discharge. Wait for5 s before removing the assembled inhaler from the adapter.Repeat the procedure. The number of discharges should beminimised and typically would not be greater than 10. Thenumber of discharges is sufficient to ensure an accurate andprecise determination of the fine particle dose. After thefinal discharge, wait for 5 s and then switch off the pump.

Dismantle the apparatus. Carefully remove the filter andextract the active substance into an aliquot of the solvent.Remove the induction port and mouthpiece adapter from theapparatus and extract the active substance into an aliquotof the solvent. Extract the active substance from the innerwalls and the collection plate of each of the stages of theapparatus into aliquots of solvent.



Procedure for powder inhalers

The aerodynamic cut-off diameters of the individual stagesof this apparatus are currently not well-established at flowrates other than 28.3 litres/min. Users must justify andvalidate the use of the impactor in the chosen conditions,when flow rates different from 28.3 litres/min are selected.

Assemble the Andersen impactor with the pre-separator anda suitable filter in place and ensure that the system is airtight.Depending on the product characteristics, the pre-separatormay be omitted, where justified and authorised. Stages 6and 7 may also be omitted at high flow rates, if justified. Thepre-separator may be coated in the same way as the platesor may contain 10 ml of a suitable solvent. Connect theapparatus to a flow system according to the scheme specifiedin Figure 2.9.18.-8 and Table 2.9.18.-4.Unless otherwise defined, conduct the test at the flowrate, Qout, used in the test for uniformity of delivered dosedrawing 4 litres of air from the mouthpiece of the inhalerand through the apparatus.Connect a flowmeter to the induction port. Use a flowmetercalibrated for the volumetric flow leaving the meter, orcalculate the volumetric flow leaving the meter (Qout) usingthe ideal gas law. For a meter calibrated for the enteringvolumetric flow (Qin), use the following expression :



Adjust the flow control valve to achieve steady flow throughthe system at the required rate, Qout (± 5 per cent). Ensurethat critical flow occurs in the flow control valve by theprocedure described for Apparatus C. Switch off the pump.



Prepare the powder inhaler for use according to thepatient instructions. With the pump running and the 2-waysolenoid valve closed, locate the mouthpiece of the inhalerin the mouthpiece adapter. Discharge the powder intothe apparatus by opening the valve for the required time,T (± 5 per cent). Repeat the discharge sequence. The numberof discharges should be minimised and typically would notbe greater than 10. The number of discharges is sufficientto ensure an accurate and precise determination of fineparticle dose.

Dismantle the apparatus. Carefully remove the filter andextract the active substance into an aliquot of the solvent.Remove the pre-separator, induction port and mouthpieceadapter from the apparatus and extract the active substanceinto an aliquot of the solvent. Extract the active substancefrom the inner walls and the collection plate of each of thestages of the apparatus into aliquots of solvent.



APPARATUS E

Apparatus E is a cascade impactor with 7 stages and amicro-orifice collector (MOC). Over the flow rate range of30 litres/min to 100 litres/min the 50 per cent-efficiencycut-off diameters (D50 values) range between 0.24 µm to11.7 µm, evenly spaced on a logarithmic scale. In this flowrange, there are always at least 5 stages with D50 values

between 0.5 µm and 6.5 µm. The collection efficiency curvesfor each stage are sharp and minimise overlap betweenstages.Material of construction may be aluminium, stainless steelor other suitable material.The impactor configuration has removable impaction cupswith all the cups in one plane (Figures 2.9.18.-11/14). Thereare 3 main sections to the impactor ; the bottom frame thatholds the impaction cups, the seal body that holds thejets and the lid that contains the interstage passageways(Figures 2.9.18.-11/12). Multiple nozzles are used at all butthe first stage (Figure 2.9.18.-13). The flow passes throughthe impactor in a saw-tooth pattern.Critical dimensions are provided in Table 2.9.18.-6.In routine operation, the seal body and lid are held togetheras a single assembly. The impaction cups are accessiblewhen this assembly is opened at the end of an inhaler test.The cups are held in a support tray, so that all cups can beremoved from the impactor simultaneously by lifting out thetray.An induction port with internal dimensions (relevant to theairflow path) defined in Figure 2.9.18.-7 connects to theimpactor inlet. A pre-separator can be added when required,typically with powder inhalers, and connects between theinduction port and the impactor. A suitable mouthpieceadapter is used to provide an airtight seal between theinhaler and the induction port.Apparatus E contains a terminal Micro-OrificeCollector (MOC) that for most formulations will eliminate theneed for a final filter as determined by method validation.The MOC is an impactor plate with nominally 4032 holes,

Figure 2.9.18.-11. – Apparatus E (shown with the pre-separator in place)



Figure 2.9.18.-12. – Apparatus E showing component parts

Stage 452 holes

Figure 2.9.18.-13. – Apparatus E: nozzle configuration

Figure 2.9.18.-14. – Apparatus E: configuration of interstage passageways

each approximately 70 µm in diameter. Most particles notcaptured on stage 7 of the impactor will be captured onthe cup surface below the MOC. For impactors operated at60 litres/min, the MOC is capable of collecting 80 per centof 0.14 µm particles. For formulations with a significant

fraction of particles not captured by the MOC, there is anoptional filter holder that can replace the MOC or be placeddownstream of the MOC (a glass fibre filter is suitable).Procedure for pressurised inhalersPlace cups into the apertures in the cup tray. Insert the cuptray into the bottom frame, and lower into place. Close theimpactor lid with the seal body attached and operate the



handle to lock the impactor together so that the system isairtight.

Table 2.9.18.-6. – Critical dimensions for apparatus E

Description Dimension(mm)

Pre-separator (dimension a - see Figure 2.9.18.-15) 12.8 ± 0.05

Stage 1* Nozzle diameter 14.3 ± 0.05







MOC* approx. 0.070

Cup depth (dimension b - see Figure 2.9.18.-14) 14.625 ± 0.10

Collection cup surface roughness (Ra) 0.5 - 2 µm

Stage 1 nozzle to seal body distance** - dimension c 0 ± 1.18

Stage 2 nozzle to seal body distance** - dimension c 5.236 ± 0.736






MOC nozzle to seal body distance** - dimension c 14.429 to 14.571

* See Figure 2.9.18.-13** See Figure 2.9.18.-14

Connect an induction port with internal dimensions definedin Figure 2.9.18.-7 to the impactor inlet. Place a suitablemouthpiece adapter in position at the end of the induction

port so that the mouthpiece end of the actuator, wheninserted, lines up along the horizontal axis of the inductionport. The front face of the inhaler mouthpiece must be flushwith the front face of the induction port. When attached tothe mouthpiece adapter, the inhaler is positioned in the sameorientation as intended for use. Connect a suitable pump tothe outlet of the apparatus and adjust the air flow throughthe apparatus, as measured at the inlet to the induction port,to 30 litres/min (± 5 per cent). Switch off the pump.Unless otherwise prescribed in the patient instructions,shake the inhaler for 5 s and discharge 1 delivery to waste.Switch on the pump to the apparatus. Prepare the inhalerfor use according to the patient instructions, locate themouthpiece end of the actuator in the adapter and dischargethe inhaler into the apparatus, depressing the valve for asufficient time to ensure a complete discharge. Wait for 5 sbefore removing the assembled inhaler from the adapter.Repeat the procedure. The number of discharges should beminimised, and typically would not be greater than 10. Thenumber of discharges is sufficient to ensure an accurate andprecise determination of the fine particle dose. After thefinal discharge, wait for 5 s and then switch off the pump.Dismantle the apparatus and recover the active substanceas follows : remove the induction port and mouthpieceadapter from the apparatus and recover the deposited activesubstance into an aliquot of solvent. Open the impactor byreleasing the handle and lifting the lid. Remove the cup tray,with the collection cups, and recover the active substance ineach cup into an aliquot of solvent.Using a suitable method of analysis, determine the quantityof active substance contained in each of the aliquots ofsolvent.Calculate the fine particle dose (see Calculations).

Procedure for powder inhalersAssemble the apparatus with the pre-separator(Figure 2.9.18.-15). Depending on the productcharacteristics, the pre-separator may be omitted, wherejustified.

Figure 2.9.18.-15. – Apparatus E: pre-separator configuration



Place cups into the apertures in the cup tray. Insert the cuptray into the bottom frame, and lower into place. Close theimpactor lid with the seal body attached and operate thehandle to lock the impactor together so that the system isairtight.

When used, the pre-separator should be assembled as follows :assemble the pre-separator insert into the pre-separator base.Fit the pre-separator base to the impactor inlet. Add 15 mlof the solvent used for sample recovery to the central cup ofthe pre-separator insert. Place the pre-separator body on topof this assembly and close the 2 catches.

Connect an induction port with internal dimensions definedin Figure 2.9.18.-7 to the impactor inlet or pre-separatorinlet. Place a suitable mouthpiece adapter in position at theend of the induction port so that the mouthpiece end of theinhaler, when inserted, lines up along the horizontal axis ofthe induction port. The front face of the inhaler mouthpiecemust be flush with the front face of the induction port. Whenattached to the mouthpiece adapter, the inhaler is positionedin the same orientation as intended for use. Connect theapparatus to a flow system according to the scheme specifiedin Figure 2.9.18.-8 and Table 2.9.18.-4.

Unless otherwise prescribed, conduct the test at the flowrate, Qout, used in the test for uniformity of delivered dosedrawing 4 litres of air from the mouthpiece of the inhalerand through the apparatus. Connect a flowmeter to theinduction port. Use a flowmeter calibrated for the volumetricflow leaving the meter, or calculate the volumetric flowleaving the meter (Qout) using the ideal gas law. For a metercalibrated for the entering volumetric flow (Qin), use thefollowing expression :



Adjust the flow control valve to achieve steady flow throughthe system at the required rate, Qout (± 5 per cent). Ensurethat critical flow occurs in the flow control valve by theprocedure described for Apparatus C. Switch off the pump.Prepare the powder inhaler for use according to thepatient instructions. With the pump running and the 2-waysolenoid valve closed, locate the mouthpiece of the inhalerin the mouthpiece adapter. Discharge the powder intothe apparatus by opening the valve for the required time,T (± 5 per cent). Repeat the discharge sequence. The numberof discharges should be minimised and typically would notbe greater than 10. The number of discharges is sufficientto ensure an accurate and precise determination of fineparticle dose.Dismantle the apparatus and recover the active substance asfollows : remove the induction port and mouthpiece adapterfrom the pre-separator, when used, and recover the depositedactive substance into an aliquot of solvent. When used,remove the pre-separator from the impactor, being careful toavoid spilling the cup liquid into the impactor. Recover theactive substance from the pre-separator.Open the impactor by releasing the handle and lifting the lid.Remove the cup tray, with the collection cups, and recoverthe active substance in each cup into an aliquot of solvent.Using a suitable method of analysis, determine the quantityof active substance contained in each of the aliquots ofsolvent.Calculate the fine particle dose (see Calculations).

Table 2.9.18.-7. – Calculations for Apparatus C. Use q = , where Q is the test flow rate in litres per minute(Qout for powder inhalers)

Cut-off diameter(µm)

Mass of active substance depositedper discharge

Cumulative mass of active substancedeposited per discharge

Cumulative fraction of active substance(per cent)

d4 = 1.7 × q mass from stage 5, m5* c4 = m5 f4 = (c4/c) × 100

d3 = 3.1 × q mass from stage 4, m4c3 = c4 + m4 f3 = (c3/c) × 100

d2 = 6.8 × q mass from stage 3, m3c2 = c3 + m3 f2 = (c2/c) × 100

mass from stage 2, m2c = c2 + m2 100

* Stage 5 is the filter stage

Table 2.9.18.-8. – Calculations for Apparatus D when used at a flow rate of 28.3 litres/min


Mass of active substance depositedper discharge


Cumulative fraction of activesubstance (per cent)

d7 = 0.4 mass from stage 8, m8c7 = m8 f7 = (c7/c) × 100

d6 = 0.7 mass from stage 7, m7c6 = c7 + m7 f6 = (c6/c) × 100









EUROPEAN PHARMACOPOEIA 5.1 2.9.26. Specific surface area by gas adsorption

CALCULATIONSFrom the analysis of the solutions, calculate the mass ofactive substance deposited on each stage per discharge andthe mass of active substance per discharge deposited in theinduction port, mouthpiece adapter and when used, thepre-separator.Starting at the final collection site (filter or MOC),derive a table of cumulative mass versus cut-offdiameter of the respective stage (see Tables 2.9.18.-7for Apparatus C, 2.9.18.-8 for Apparatus D, 2.9.18.-9 for

Apparatus E). Calculate by interpolation the mass of theactive substance less than 5 µm. This is the Fine ParticleDose (FPD).

If necessary, and where appropriate (e.g., where there is alog-normal distribution), plot the cumulative fraction of activesubstance versus cut-off diameter (see Tables 2.9.18.-7/9)on log probability paper, and use this plot to determinevalues for the Mass Median Aerodynamic Diameter (MMAD)and Geometric Standard Deviation (GSD) as appropriate.Appropriate computational methods may also be used.

Table 2.9.18.-9. – Calculations for Apparatus E. Use q = (60/Q)x, where Q is the test flow rate in litres per minute,and x is listed in the table


x Mass of active substancedeposited per discharge


Cumulative fraction of activesubstance (per cent)

d7 = 0.34 × q 0.67 mass from MOC or terminalfilter, m8

c7 = m8 F7 = (c7/c) × 100

d6 = 0.55 × q 0.60 mass from stage 7, m7c6 = c7 + m7 F6 = (c6/c) × 100







04/2005:20926

2.9.26. SPECIFIC SURFACE AREA BYGAS ADSORPTION

INTRODUCTION

The specific surface area of a powder is determined byphysical adsorption of a gas on the surface of the solid andby calculating the amount of adsorbate gas corresponding toa monomolecular layer on the surface. Physical adsorptionresults from relatively weak forces (van der Waals forces)between the adsorbate gas molecules and the adsorbentsurface of the test powder. The determination is usuallycarried out at the temperature of liquid nitrogen. Theamount of gas adsorbed can be measured by a volumetric orcontinuous flow procedure.

BRUNAUER, EMMETT AND TELLER (BET) THEORY ANDSPECIFIC SURFACE AREA DETERMINATION

MULTI-POINT MEASUREMENTThe data are treated according to the Brunauer, Emmett andTeller (BET) adsorption isotherm equation :

(1)

P = partial vapour pressure of adsorbate gas inequilibrium with the surface at 77.4 K (b.p. ofliquid nitrogen), in pascals,

Po= saturated pressure of adsorbate gas, in pascals,

Va= volume of gas adsorbed at standard temperature

and pressure (STP) [273.15 K and atmosphericpressure (1.013 × 105 Pa)], in millilitres,

Vm= volume of gas adsorbed at STP to produce an

apparent monolayer on the sample surface, inmillilitres,

C = dimensionless constant that is related to theenthalpy of adsorption of the adsorbate gas onthe powder sample.

A value of Va is measured at each of not less than 3 values ofP/Po.Then the BET value

is plotted against P/Po according to equation (1). Thisplot should yield a straight line usually in the approximaterelative pressure range 0.05 to 0.3. The data are consideredacceptable if the correlation coefficient, r, of the linearregression is not less than 0.9975 ; that is, r2 is not less than0.995. From the resulting linear plot, the slope, which isequal to (C −1)/VmC, and the intercept, which is equal to1/VmC, are evaluated by linear regression analysis. Fromthese values, Vm is calculated as 1/(slope + intercept), whileC is calculated as (slope/intercept) + 1. From the value ofVm so determined, the specific surface area, S, in m2·g–1, iscalculated by the equation :

(2)

N = Avogadro constant (6.022 × 1023 mol−1),a = effective cross-sectional area of one adsorbate

molecule, in square metres (0.162 nm2 fornitrogen and 0.195 nm2 for krypton),

m = mass of test powder, in grams,

22400 = volume occupied by 1 mole of the adsorbategas at STP allowing for minor departures fromthe ideal, in millilitres.


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