J P Gupta, P V Joshi, P V N Nair & K S V Nambi Environmental Assessment Division, Bhabha Atomic Research Centre, Trombay, Bombay , India

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1 Indian Jurnal f Chemical Technlgy Vl., September 1995,pp Characterisatin f medicinal aersls J P Gupta, P V Jshi, P V N Nair & K S V Nambi Envirnmental Assessment Divisin, Bhabha Atmic Research Centre, Trmbay, Bmbay 4 85, India Fur cmmercially available medicinal aersl prducts in India have been assessed fr the aersl size distributin at tw different humidities using a ten stage cascape impactr device having a quartz crystal micrbalance system. An indigenusly made nebulizer in use in a city hspital has als been assessed fr its aersl efficiency. The size range is between.5 and 5 J.l,m. Mde in the aersl mass size distributin is between.4 and 1.6 J.l,m at 3% relative humidity (RH) and between.4 and 3. J.l,m at 85% RH fr three inhalers: the mde fr pwder inhaler is between 3. and 6.4 J.l,m at 3% RH and 5 J.l,m at 85% RH. The mde fr indiginus nebulizer is between.5 and.1 J.l,m. These results are discussed in the cntext f the depsitin f aersls in the human respiratry system. Recently, medicatin thrugh the respiratry tract in selected diseases has gained cnsiderable ppularity due t factrs such as easy applicatin, lack f side effects, ecnmic and efficient use f the medicine and better respnse. The medicine is intrduced int the respiratry system as an aersl by the use f a nebulizer r utilizing medicinal aersl packages cnsisting f medicine mixed with a prpellant gas and prvided with a cntrl valve fr dse inhalatin t a fixed quantity f aerslised medicine. Different aspects f the use f pharmaceutical aersls are being studied in varius labratries1-s allver the wrld f understand and imprve its perfrmance. Fr the effective treatment f respiratry tract ailments, it is essential t learn the mechanism and the degree f aersl penetratin in lungs and their absrptin. Data n size distributin and cncentratin f medicinal aersl are scarce and classified; the cmmercially available medicinal aersls need t be characterised t enable an estimatin f the site and efficiency f depsitin in the respiratry system. A few f the cmmn medicines in aers91 frm frequently used by physicians in' India have been analysed fr their particle size distributin. Depsitin in Respiratry Tract On the basis f the structure, air flw pattern, functin and sensitivity t depsiting particles, the respiratry tract has been divided int different regins, i.e.,.naspharyngeal (NP), Trachebrncheal (TB) and Pulmnary (P), fr mdelling f depsitin and clearance f airbrne particles 1 In a recent mdel, the NP regin has been extended t ral passage and it is called as Ex-trathracic (ET) regin. The TB regin is divided int brnchi (BB) and brnchiles (bb) regins and gas-exchange regin is called as alvelar interstitial (AI). The depsitin f the particles in respiratry tract takes place by impactin, sedimentatin and diffusin The impactin is the primary mechanism f depsitin in the large airways, sedimentatin is the mst efficient mechanism in the smaller airways and the alvelar regin, where air velcity is lw and airways dimensins are smali 3. Diffusinal depsitin is the predminant mechanism fr particles smaller than.5,urn in diameter and is gverned by gemetrical rather than aerdynamic size. The depsitin f inhaled particles als depends upn breathing rate, inhalatin vlume and the length f retentin f breath. The depsitin f the different size aersls in lung's three different cmpartments has been drawn graphically and shwn in Fig. 1. In this figure, terms AMID and AMAD are defined as activity median thermdy- 1. z Ger ET 51 ti <C.1 I&. u iii. a. I +--MAD. -. Fig. I-Reginal depsitin fractins f inhaled aersls

2 1 'I " I 8 INDIAN 1. CHEM. TECHNOL., SEPTEMBER 1995 CJ PROCESSING ELECTRONICS FLASK Fig. -Schematic f the aersl measurement system Table 1- Medicinal aersls tested fr their efficiency Name fthe cmpany Glax Cipla Name f the Medicinal aersl Salbutaml Sdium Crmglycate Cipla Beclamethasne Diprpinate Cipla Salbutaml Sulphate Nte: The results n the abve medicines are presented in the paper withut identifying the manufacturer. namic diameter and activity median aerdynamic diameter respectively. Experimental Prcedure A ten stage cascade impactr device using Quartz Crystal Micrbalance6 (OCM) system has been used t analyse the size distributin f medicinal aersls. Fig., shws a schematic f the experimental system used fr this analysis. The size seperatin f particles is dne by impactin The apparatus directly gives a spectrum giving mass cncentratin f particles in 1 stages; each stage is designated by the size fr which it is having 5% prbability f capture f particles f a specified mass density. Fur medicinal aersls generally used fr respiratry tract therapy have been analysed (Table 1). :Fr bvius reasns, their identities with the btained results are nt indicated. Three f these medicines are in liquid r semi-liquid frm filled in pressurised can with facility fr intrducing them int muth. While the furth ne is a pwder. The pwdered medicine cmes in capsules. The medicine is inhaled with the help f rtahaler. During aersl therapy the patient is asked t intrduce the aerslised medicine thrugh the muth piece f the canister and inhale slwly. As shwn in Fig., a tw litre flask fr, cllecting these aersls fr measurements has been used. Tw ets f readings have been taken with each medicine: (i) intrducing in a flflsk having rm air f 3% humidity, (ii) intrducing in the flask air which is usually misturised t abut 85% humidity7. The measurements at tw humidities have been carried ut t study variatin in size distributin due t change in RH f t inhaled air. Very large aersls quickly depsit in the neck f the flask and whatever remain suspended are measured by the QCM. The sampling time f these aersls fr analysis by the OCM depends upn the cncentratin and it varies frm 5 s t a few minutes. Other systems are als used fr generating the medicinal aersls fr inhalatin by patients. One such system was received frm a hspital at Jabalpur fr characterisatin f aersls generated frm its nebulizer. The system is shwn in the }?htgraph in Fig. 3. The nebulizer is perated by a pedalling pump and the medicines disslved in distilled water are kept in the nebulizer can. Aersls have als been prduced frm pure distilled water nly. The same flask shwn in Fig., was filled with aersls cming ut frm nebulizer and measured by OCM. Results and Discussin The results f these measurements are shwn in Figs 4-7. In Figs 4a, 5a, 6a and 7a, tw graphs f aersl size distributin are shwn: the lwer ne fr rm air (3% RH) in flask and the upper ne fr medicinal aersl after pumping them in the flask frm inhaler. The size distributin f aersl particles in rm air is nt the same in each case, because it depends upn several parameters f the rm air. Similarly in Figs 4b, 5b, 6b and 7b, the lwer graph shws the aersl size distributin in mist air (85% RH) in the flask and upper ne after pumping the medicinal aersls frm inhaler int the same mist flask. On the abscisae the mass median diameter separated by each stage f OCM are shwn. \ I" '1,1 ""\'p'i'i I 1 "

GUPTA et at.: MEDICINAL AEROSOLS 83 3..... Z u i:z:...., 'Q: e «, <!) E... 1.. Z.. z UJ uz u 4 "'E 3 «, x 1 ROOM AIR ọ 3.5 1, 8 1.6 3 6.4 1.5 5 SO SIZE, p'm Fig.

3 GUPTA et at.: MEDICINAL AEROSOLS Z u i:z:...., 'Q: e «, <!) E Z.. z UJ uz u 4 "'E 3 «, x 1 ROOM AIR ọ 3.5 1, SO SIZE, p'm Fig. 4a-Aersl mass size distributin in ne puff f Inhaler-I and in AC rm air (3% RH)... l!1& Fig. 3 - Manual aersl generatr used in a hspital Inhaler-I is in the frm f thick slutin and releases 5 mg f medicine in ne metered dse. Mst f the aersl particles released frm this inhaler are f very large size (> 5,urn) and they quickly fall in the neck and n glass bdy f the flask and inside f the glass tube leading t QCM. Depsitin f the aersl particles n glass surface f the flask can be bserved visually. Fig. 4a shws the particle size distributin and their relative mass cncentratins after 15- s f pumping in the flask. The graph clearly' shws that the maximum cncentratin is arund ,um size particles. There are sme large size (arund 5,urn) particles als. These particles must have frmed by cagulatin n the way during the prcess f cllectin by QCM cascade impactr fr measurement. Fig. 4b shws the size distributin and mass cncentratin f the same medicinal aersl particles in misturised atmsphere. The cmparisn f tw sets f grups shws a slight shift in size cncentratin but a big reductin in mass cncentratin. This may be due t faster grwth in the misturised air t frm large size particles which quickly settle dwn. Majr frac- N ;;; J1 u' -.. le I e 9 4 ffi.. Z!!C 14 1 u u,8 e c :1 «le 4 MOISTURISED AIR ọ S SIZE, p'm Fig. 4b-Aersl size distributin in 85% RH air and in ne puff f misturised aersls frm Inhaler-I. tin f aersls frm this inhaler will get trapped in the extrathracic (ET) regin since they are f larger than lo,um size. The particles f smaller than 3,urn size will pass thrugh trachebrnchial regin and smaller than 1,urn size will reach the pulmnary regin.

4 84 INDIAN J. CHEM. TECHNOL., SEPTEMBER Ill:!Z E 53 : :z: ui!: " CL. 9 ell 31-1 (:1- ROOM AIR 31 Ill: 4 z..j e..j 1! N l!) - E : u WQ. (...J, E l- it : :E ( in ell', - uroom AIR 1 I SO C % SIZE. fill Fig. Sa-Aersl mass size distributin in, ne puff f Inhaler-II arid in AC rm air (3% RH) MO/SlURISED AIR SIZE'P.m Fig. 5b-Aersl mass size distributin in 8S% RH air and in ne puff f misturised aersls frm Inhaler-II In inhaler-il, the medicinal particles are suspended in an inert prpellant. In each puff f inhaler 1 p,g f medicine in the frm f aersl particles is released alng with the prpellants. The measurement f particle size and their mass distributin is again carried ut in the same way after injecting the medicine in flask frm the can a SIZE'l1m Fig. 6a - Aersl mass size distributin in ne puff f Inhaler and in AC rm air (3% RH)..J... ;!!: 1 N in 8 % X e!:.. 6 «e..j 4.. Z : u 5r,.---, MOISTURISED AIR u e «:E SIZE.\1m Fig. 6b-'Aersl mass size distributin in 85% RH air and in ne puff f mistured aersls frm Inhaler-. The neck f the flask and the bdy d nt shw any depsitin f large size particles in the first few minutes. The results are shwn in Fig. Sa. This figure clearly shws that the majrity f the aersls are arund.8 and 1.6 p,m size and the cncentratin is als quite lw as each puff cnsists f nly 1 p,g f medicine. Large size parti- \ II I.' "1'\' '1'1

5 GUPTA et al.: MEDICINAL AEROSOLS iii zn..je 1 6 ĪII ru 4 Zu.... E Z 4 Z ce ::EO 8..J... N e in E u.. r 6.. ii: C 9 4 z!e 1 uz U ::L ::E U I,--, II E e... ROOM AIR ' ' ZE I flm Fig. 7a-Aersl mass size distributin in ne dse f day pwder inhaler and in AC rm air (3% RH). MOI5TURI5ED AIR 51ZE. P. m Fig. 7b-Aersl mass size distributin in 85% RH air and in ne dse f pwder inhaler inflated in misture cles in this sample are nt at all present. Fig. 5b shws the spectrum f aersl size distributin and their mass cncentratin in the presence f misture. Misture clearly influences the medicinal aersls t frm large size particles. Frmatin f large size particles leads t the reductin in the mass cncentratin due t faster settling as can be seen frm the graph. The aersls frm this inhaler will easily reach trachebrnchial and pulmnary regins. Inhaler- releases,ug aerslised medicine in ne puff. The results f measurement f this medicine are shwn in Figs 6a and 6b. Mst f the aersls prduced by this inhaler are f very small size, mainly between.3 and.8,um. There are sme traces f large size particles als. Since these aersl particles are f smaller sizes and their cncentratin is als lw, there is nt much influence f misture n them, hwever the increase in the ttal cncentratin and slight change in their size spectrum can be nticed. The medicinal aersls frm this inhaler will quickly reach pulmnary regins. The furth medicine is a dry pwder filled in capsules. Each capsule cntains,ug f this pwder. This pwder in the capsule is inhaled with the help f rtahaler by the patient. The particles in the pwder are f very large size (> 5,um). Their size analysis is dne by sieving technique. The pwder was intrduced in the flask by blwing air ver the sample kept in a tube cnnected t the flask. A small number f particles which remained suspended in the flask are cllected and measured by QCM. The results are shwn in the Fig. 7a. This figure clearly shws that the particles smaller than 1.6,um are negligible. The majrity f the particles are between 3. and 1.5,um size. Frm Fig. 7b, it can be seen that the cncentratin f the particles gets mdified in the presence f misture with the frmatin f larger size particles. The particles smaller than 1.6,um are fund t be absent. The majrity f the aersl particles in the presence f the misture are larger than 5,um. It is likely that these particles might have frmed n the way twards QCM. Mst f the particles f this medicine will get struck t thrat and the left ver particles will get trapped in the trachea. The results f manually perated nebulizer using distilled water are shwn in Fig. 8. The aersls prduced frm this nebulizer are frm.3 t.,um diameter. Since the aersl prduced frm this system are inhaled thrugh nse, the large size ( 1.5,um) will get trapped in nse itself. A cnsiderable fractin f the fine aersl will reach trachebrnchial and pulmnaryregins easily. It is bserved that the paddling speed

6 86 INDIAN J. CHEM. TECHNOL., SEPTEMBER 1995.j ẕ w 1. N in u "'eo.!=: " «e <l).6.j w., ẉ.. CL z.... z w Z u 4 - ROOM AIR cines being used fr the treatment f the respiratry tract ailments. The study has clearly brught ut instances where a majr quantity f the medicine is lst in the upper respiratry ways. Medical practitiners can plan the line f treatment after knwing the size distributin f the aersls available frm the inhaler. Such studies will als help the pharmaceutical cmpanies t adpt suitable manufacturing prcesses fr prductin f apprpriate size spectrum f aerslised medicine. Acknwledgement The authrs wish t thank Dr (Ms) R V Chugule, Pulmnary Physician, Bmbay Hspital, Bmbay fr suggesting the prblem, prviding the necessary samples and generatr and fr useful discussins during the investigatins SIZE, pm Fig. 8-Mass size distributin f distilled water aersls prduced by manually perated nebulizer and f AC rm air (3% RH) f the pump des nt change the size distributin f aersls. It nly changes the cncentratin. Cnclusins The wrk reprted here gives an idea f the size distributin f particles in aerslised medi- References 1 Baily M R & Birchall A, NRPB Radi Prtect sia; 119 (1991)13. Hinds W C, Aersl technlgy (Jhn Wiley & Sns, New Yrk), 198,11. 3 Stahlhfen W, Gebhart J, Heyder & Scheuch G, J Aersl Sci, 14 (1983) Heyder J, Armbruster L, Gebhart I, Grein E & Stahlhfen W, J Aersl Sci; 6 (1975) Hiller F C, Mazumder M K, Wilsn J, McLed P C & Bne R C, J Aersl Sci; 13 (198) Lundgren A, Harris Jr F S, Marlw W H, Lippman, Clark W E & Durham M D, Aersl measurement (University Press Flrida, Gainesville), 1979, Martnen T B & Wilsn A F, J Aersl Sci, 14 (1983) 8.

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