');--grs:50px;--gtaos:105px;--gtaosi:-105px;--gtaof:210px;--gbes:calc(100% + 105px);--gbef:calc(100% + 210px);--gbet:translateX(-105px);--gbeti:translateX(105px);--vgc:repeat(12, 1fr);--gc1:repeat(12, 1fr);--gc2:repeat(6, 1fr);--gc3:repeat(4, 1fr);--gc3h:1/4;--gc4:repeat(3, 1fr);--gcm:8.333%;--gac:1fr;--gcw50:50%;--gc2tp:0 calc(var(--grs) * 2) 0 0;--gc2sw:var(--gbes);--gc2slpl:0 0 0 105px;--gc2srpf:0 105px 0 0;--gc2sof:1;--gc2sol:2;--gc50:4/span 6;--gc48a:1/5;--gc48b:5/-1;--gc84a:1/9;--gc84b:9/-1;--gc39a:1/4;--gc39b:4/-1;--gc93a:1/10;--gc93b:10/-1;--gc615a:1/7;--gc615b:8/-1;--gc516a:1/6;--gc516b:7/-1;--tppr:0;--bgp:42px;--s_cn:0;--s_ces:4px;--s_cest:4px 4px 0 0;--s_cesb:0 0 4px 4px;--s_cs:8px;--s_cm:12px;--s_cl:16px;--s_cls:16px 0 0 16px;--s_cle:0 16px 16px 0;--s_clt:16px 16px 0 0;--s_cel:28px;--s_celt:28px 28px 0 0;--s_cf:50%;--m_ds1:50ms;--m_ds2:100ms;--m_ds3:150ms;--m_ds4:200ms;--m_dm1:250ms;--m_dm2:300ms;--m_dm3:350ms;--m_dm4:400ms;--m_dl1:450ms;--m_dl2:500ms;--m_dl3:550ms;--m_dl4:600ms;--m_de1:700ms;--m_de2:800ms;--m_de3:900ms;--m_de4:1000ms;--m_el:0,0,1,1;--m_es:0.2,0,0,1;--m_esa:0.3,0,1,1;--m_esd:0,0,0,1;--m_ee:0.2,0,0,1;--m_eea:0.3,0,0.8,0.15;--m_eed:0.05,0.7,0.1,1;--m_elg:0.4,0,0.2,1;--m_elga:0.4,0,1,1;--m_elgd:0,0,0.2,1;--cc_w:255,255,255;--cc_b:0,0,0;--c_p:1,31,48;--c_op:255,255,255;--c_pc:203,230,253;--c_opc:1,31,48;--c_s:67,81,200;--c_os:255,255,255;--c_sc:223,224,255;--c_osc:0,9,101;--c_t:83,97,98;--c_ot:255,255,255;--c_tc:215,229,230;--c_otc:17,30,31;--c_e:179,38,30;--c_oe:255,255,255;--c_ec:249,222,220;--c_oec:65,14,11;--c_co:109,123,124;--c_b:255,255,255;--c_ob:17,30,32;--c_su:249,249,249;--c_osu:17,30,32;--c_suv:215,229,230;--c_osuv:60,73,74;--c_is:38,51,53;--c_iso:239,241,242;--c_ip:175,202,224;--c_sh:0,0,0;--c_st:1,31,48;--c_cov:187,201,202;--c_scr:0,0,0;--c_suchs:225,234,236;--c_such:231,239,241;--c_suc:245,245,245;--c_sucl:249,249,249;--c_scls:255,255,255;--c_sub:249,249,249;--c_sud:209,220,222}:root ::-webkit-scrollbar,:root ::-webkit-scrollbar-corner{background:0 0;width:9pt;height:9pt}:root ::-webkit-scrollbar-thumb{background:content-box rgb(var(--c_cov));border:2px solid transparent;border-radius:8px;color:rgb(var(--c_cov));min-height:3pc;min-width:3pc}:root ::-webkit-scrollbar-button{height:0;width:0}body,frameset{padding:0;margin:0;color:rgb(var(--c_ob));background:rgb(var(--c_b));font-family:var(--t_bmf);font-size:var(--t_bms);line-height:var(--t_bmlh);font-weight:var(--t_bmw);letter-spacing:var(--t_bmt)}body{--space_nav_top:0px;--space_nav_bottom:0px;--space_nav_left:0px;--space_nav_right:0px;--DAB:0px;--CXZ:visible;overflow-x:hidden;overflow-y:var(--CXZ)}footer,header{display:flex;justify-content:flex-start}score-pointer{z-index:11000}addium-header .main *,addium-menu-footer p,addium-menu-footer p *,score-text *{-webkit-user-select:text!important;-moz-user-select:text!important;user-select:text!important}:root{--t_dlf:var(--t_tb);--t_dllh:68px;--t_dls:63px;--t_dlt:-0.5px;--t_dlw:400;--t_dmf:var(--t_tb);--t_dmlh:42px;--t_dms:35px;--t_dmt:0.25px;--t_dmw:400;--t_hlf:var(--t_tp);--t_hllh:42px;--t_hls:35px;--t_hlt:0.25px;--t_hlw:400;--t_hmf:var(--t_tp);--t_hmlh:27px;--t_hms:21px;--t_hmt:0.25px;--t_hmw:400;--t_tlf:var(--t_tm);--t_tllh:24px;--t_tls:16px;--t_tlt:0.15px;--t_tlw:500;--t_tmf:var(--t_tm);--t_tmlh:normal;--t_tms:13px;--t_tmt:0.45px;--t_tmw:500;--t_llf:var(--t_tp);--t_lllh:16px;--t_lls:12px;--t_llt:0.5px;--t_llw:500;--t_lmf:var(--t_tp);--t_lmlh:16px;--t_lms:11px;--t_lmt:0.5px;--t_lmw:500;--t_blf:var(--t_tp);--t_bllh:30px;--t_bls:21px;--t_blt:0.1px;--t_blw:400;--t_bmf:var(--t_tp);--t_bmlh:24px;--t_bms:17px;--t_bmt:0.1px;--t_bmw:400;--grs:50px;--gtaos:105px;--gtaosi:-105px;--gtaof:210px;--gbes:calc(100% + 105px);--gbef:calc(100% + 210px);--gbet:translateX(-105px);--gbeti:translateX(105px);--vgc:repeat(4, 1fr);--gc1:1fr;--gc2:1fr;--gc3:1fr;--gc3h:1/-1;--gc4:1fr 1fr;--gc5:1fr;--gcm:8.333%;--gac:auto;--gcw50:100%;--gc2tp:0;--gc2sw:100%;--gc2slpl:calc(var(--grs) / 2) 0;--gc2srpf:calc(var(--grs) / 2) 0;--gc2sof:2;--gc2sol:1;--gc50:1/-1;--gc48a:1/-1;--gc48b:1/-1;--gc84a:1/-1;--gc84b:1/-1;--gc39a:1/-1;--gc39b:1/-1;--gc93a:1/-1;--gc93b:1/-1;--gc615a:1/-1;--gc615b:1/-1;--gc516a:1/-1;--gc516b:1/-1;--bgp:18px}main{width:100%}addium-header score-form[type="0"] score-input-container.col-1,addium-header score-form[type="0"] score-input-container.col-2,addium-header score-form[type="0"] score-input-container.col-3,addium-header score-form[type="0"] score-input-container.col-4,addium-header score-form[type="0"] score-input-container.col-5,addium-header score-form[type="1"] score-input-container.col-1,addium-header score-form[type="1"] score-input-container.col-2,addium-header score-form[type="1"] score-input-container.col-3,addium-header score-form[type="1"] score-input-container.col-4,addium-header score-form[type="1"] score-input-container.col-5,addium-header score-form[type="2"] score-input-container.col-1,addium-header score-form[type="2"] score-input-container.col-2,addium-header score-form[type="2"] score-input-container.col-3,addium-header score-form[type="2"] score-input-container.col-4,addium-header score-form[type="2"] score-input-container.col-5,addium-header score-form[type="3"] score-input-container.col-1,addium-header score-form[type="3"] score-input-container.col-2,addium-header score-form[type="3"] score-input-container.col-3,addium-header score-form[type="3"] score-input-container.col-4,addium-header score-form[type="3"] score-input-container.col-5,score-banner-element section p,score-dialog-element fieldset,score-dialog-element section p,score-input-container.col-1 score-input,score-input-container.col-2 score-input,score-input-container.col-3 score-input,score-input-container.col-4 score-input,score-input-container.col-5 score-input,score-input.DJE input,score-input.DJF input,score-input.DJG input,score-input.DJH input,score-input.DJL input,score-input.DJM input,score-install section p,score-loader section p,score-push-notification section p,score-sidesheet-drawer section p{margin:0}addium-header score-form label,score-input.hidden,score-select.hidden,score-textarea.hidden{display:none!important}addium-header[type="0"] figure,addium-header[type="1"] figure,score-form[type="6"],score-form[type="7"]{padding:0}addium-header{--hm:-54px;--hp:6px;--hw:calc(100% + 108px);--hmm:108px;--hmw:calc(100% - var(--hmm));--h1mw:725px;view-transition-name:header;display:grid;grid-template-columns:var(--vgc);grid-column:1/-1;width:100%}addium-header.inverted,addium-header[type="0"],body.dark{--cc_w:255,255,255;--cc_b:0,0,0;--c_p:223,224,255;--c_op:24,51,69;--c_pc:48,74,92;--c_opc:203,230,253;--c_s:189,194,255;--c_os:5,23,154;--c_sc:40,54,175;--c_osc:223,224,255;--c_t:187,201,202;--c_ot:38,51,52;--c_tc:60,73,74;--c_otc:215,229,230;--c_e:242,184,181;--c_oe:96,20,16;--c_ec:140,29,24;--c_oec:249,222,220;--c_co:133,147,148;--c_b:0,0,0;--c_ob:219,228,230;--c_su:8,21,24;--c_osu:219,228,230;--c_suv:60,73,74;--c_osuv:187,201,202;--c_is:219,228,230;--c_iso:38,51,53;--c_ip:72,97,117;--c_sh:0,0,0;--c_st:223,224,255;--c_cov:60,73,74;--c_scr:0,0,0;--c_suchs:42,55,57;--c_such:31,44,47;--c_suc:21,34,36;--c_sucl:17,30,32;--c_scls:4,16,18;--c_sub:46,59,62;--c_sud:8,21,24}addium-header score-form{width:auto;max-width:450px;padding:28px 0!important}addium-header score-form score-input input{--cw:0!important}addium-header score-form[type="0"] .DJC,addium-header score-form[type="1"] .DJC,addium-header score-form[type="2"] .DJC,addium-header score-form[type="3"] .DJC,score-text td p,score-text th p{margin:0!important}addium-header score-form[type="6"],addium-header score-form[type="7"]{max-width:350px}addium-header[type="0"] .graphics3d,addium-header[type="0"] .score_media_element,addium-header[type="0"] figure,addium-header[type="1"] .graphics3d,addium-header[type="1"] .score_media_element,addium-header[type="1"] figure,addium-header[type="2"] .graphics3d,addium-header[type="2"] .score_media_element,addium-header[type="2"] figure,addium-header[type="3"] .graphics3d,addium-header[type="3"] .score_media_element,addium-header[type="3"] figure,score-teaser.GX .score_media_element{z-index:0}addium-header[type="0"] .main,addium-header[type="1"] .main,addium-header[type="2"] .main,addium-header[type="3"] .main{z-index:1;flex-direction:column}addium-header[type="0"] .main h1,addium-header[type="1"] .main h1,addium-header[type="2"] .main h1,addium-header[type="3"] .main h1{font-family:var(--t_dmf);font-size:var(--t_dms);line-height:var(--t_dmlh);font-weight:var(--t_dmw);letter-spacing:var(--t_dmt);max-width:var(--h1mw)}addium-header[type="0"],addium-header[type="1"]{grid-template-rows:repeat(6,1fr);margin:var(--hm) 0 0 var(--hm);width:var(--hw)}addium-header[type="0"] .graphics3d,addium-header[type="0"] .score_media_element,addium-header[type="0"] figure,addium-header[type="1"] .graphics3d,addium-header[type="1"] .score_media_element,addium-header[type="1"] figure{grid-area:1/1/-1/-1;margin:0;width:100%}addium-header[type="0"] .main,addium-header[type="1"] .main{display:block;grid-column:1/-1;padding:var(--hp)}addium-header[type="0"] .main{grid-row:3/-1;width:var(--hmw);margin:0 var(--hmm)}addium-header[type="1"]{width:100%;height:calc(-92px + 100vh);min-height:min-content;max-height:40pc;margin:0;padding:0}addium-header[type="1"] .main{grid-row:1/-1;align-self:center;padding:0 6px}addium-header[type="1"]>.graphics3d,addium-header[type="1"]>.score_media_element,addium-header[type="1"]>figure{left:50%}addium-header[type="1"]>.graphics3d>.graphics3d,addium-header[type="1"]>.graphics3d>.score_media_element,addium-header[type="1"]>.graphics3d>canvas,addium-header[type="1"]>.graphics3d>figure,addium-header[type="1"]>.graphics3d>picture,addium-header[type="1"]>.graphics3d>video,addium-header[type="1"]>.score_media_element>.graphics3d,addium-header[type="1"]>.score_media_element>.score_media_element,addium-header[type="1"]>.score_media_element>canvas,addium-header[type="1"]>.score_media_element>figure,addium-header[type="1"]>.score_media_element>picture,addium-header[type="1"]>.score_media_element>video,addium-header[type="1"]>figure>.graphics3d,addium-header[type="1"]>figure>.score_media_element,addium-header[type="1"]>figure>canvas,addium-header[type="1"]>figure>figure,addium-header[type="1"]>figure>picture,addium-header[type="1"]>figure>video{width:100vw;transform:translateX(-50%)}addium-header[type="1"]>.graphics3d img,addium-header[type="1"]>.graphics3d score-video,addium-header[type="1"]>.graphics3d svg,addium-header[type="1"]>.graphics3d video,addium-header[type="1"]>.score_media_element img,addium-header[type="1"]>.score_media_element score-video,addium-header[type="1"]>.score_media_element svg,addium-header[type="1"]>.score_media_element video,addium-header[type="1"]>figure img,addium-header[type="1"]>figure score-video,addium-header[type="1"]>figure svg,addium-header[type="1"]>figure video{object-fit:cover;height:calc(-92px + 100vh);max-height:40pc}addium-header[type="2"] .main,addium-header[type="3"] .main{display:block;grid-row:1/span 2}addium-header[type="2"] .main{margin:3pc 6px;width:calc(100% - 12px);grid-column:1/-1}addium-header[type="2"] .graphics3d,addium-header[type="2"] .score_media_element,addium-header[type="2"] figure{margin:0;width:calc(100% - 12px);display:block;grid-column:1/-1;grid-row-end:span 6;padding:0!important}addium-header[type="2"]+score-video-external{margin:-9pt;width:calc(100% + 24px);grid-column:1/-1}addium-header[type="3"] .main{grid-column:1/7;height:min-content;align-self:center;margin:0 6px;width:calc(100% - 12px)}addium-header[type="3"] .graphics3d,addium-header[type="3"] .score_media_element,addium-header[type="3"] figure{grid-column:7/-1}:root{--sv:visible;--tti:translate(0, 0);--ttc:translate(-50%, -50%);--ttcx:translate(-50%, 0);--ttcy:translate(0, -50%);--ttvx:translateX(-50vw);--ttl:translate(-100%, 0);--ttr:translate(100%, 0);--ttt:translate(0, -100%);--ttb:translate(0, 100%);--tra:rotate(45deg);--trb:rotate(-45deg);--trc:rotate(90deg);--trd:rotate(-90deg);--tsa:scaleX(0);--tsb:scaleX(1);--tsc:scaleY(0);--tsd:scaleY(1);--bxa:0 2px 4px -1px rgba(0, 0, 0, 0.2),0 1px 10px 0 rgba(0, 0, 0, 0.12),0 4px 5px 0 rgba(0, 0, 0, 0.14);--ba:1px solid var(--cb);--bb:1px solid var(--cw);--bc:1px solid var(--cg1);--bd:1px solid var(--cg2);--be:1px solid var(--cg4);--c_st0:0;--c_st1:0.05;--c_st2:0.08;--c_st3:0.11;--c_st4:0.12;--c_st5:0.15;--c_bs0:drop-shadow(0px 0px 0px rgba(0, 0, 0, 0.2)) drop-shadow(0px 0px 0px rgba(0, 0, 0, 0.14)) drop-shadow(0px 0px 0px rgba(0, 0, 0, 0.12));--c_bs1:drop-shadow(0px 2px 1px rgba(0, 0, 0, 0.2)) drop-shadow(0px 1px 1px rgba(0, 0, 0, 0.14)) drop-shadow(0px 1px 3px rgba(0, 0, 0, 0.12));--c_bs2:drop-shadow(0px 3px 3px rgba(0, 0, 0, 0.2)) drop-shadow(0px 3px 4px rgba(0, 0, 0, 0.14)) drop-shadow(0px 1px 8px rgba(0, 0, 0, 0.12));--c_bs3:drop-shadow(0px 3px 5px rgba(0, 0, 0, 0.2)) drop-shadow(0px 6px 10px rgba(0, 0, 0, 0.14)) drop-shadow(0px 1px 18px rgba(0, 0, 0, 0.12));--c_bs4:drop-shadow(0px 5px 5px rgba(0, 0, 0, 0.2)) drop-shadow(0px 8px 10px rgba(0, 0, 0, 0.14)) drop-shadow(0px 3px 14px rgba(0, 0, 0, 0.12));--c_bs5:drop-shadow(0px 7px 8px rgba(0, 0, 0, 0.2)) drop-shadow(0px 12px 17px rgba(0, 0, 0, 0.14)) drop-shadow(0px 5px 22px rgba(0, 0, 0, 0.12));--s_dec1:1;--s_dec2:1;--s_dc1:0.12;--s_dc2:0.38;--s_de:0;--s_ho:0.08;--s_fo:0.12;--s_po:0.12;--s_do:0.16;--s_scr:0.5;--g_l0:linear-gradient(to top, rgba(0, 0, 0, 0.5) 0, rgba(0, 0, 0, 0.15) 100%);--g_l1:linear-gradient(to top, rgba(0, 0, 0, 0.5) 0, rgba(0, 0, 0, 0) 50%);--g_l2:linear-gradient(to top, rgba(0, 0, 0, 0.66) 0, rgba(0, 0, 0, 0.33) 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Rather than measuring the total amount of water in a system, water activity measures how much of that water is unbound and free to react with other substances.
At first, the implications may seem insignificant. In application, they’re considerable. Water activity has a clear and direct influence on microbial growth, API degradation, product stability, and dissolution rates. In addition, water activity is generally a more accessible and direct method of understanding these factors than other, more time- and expertise-intensive analytical measurements.
More than a decade ago, the USP introduced General Chapter <1112>, the pharmaceutical industry’s first significant approval of water activity. The chapter describes water activity as an aid to:
The chapter also references several methods for determining water activity in the Official Methods of Analysis of AOAC International.
Supporting the USP’s recognition of water activity, the ICH laid out additional information supporting the use of water activity in Q1A, Q6A and their associated decision trees.
Over time, acceptance has grown, and with it has come the realization that while water activity saves significant time in microbial testing, the potential for profitable applications in quality testing, R&D, and other areas is just as significant.
More recently, USP has introduced two more water activity-related chapters – USP <795> and a draft of <922>. The former focuses on microbial growth and preservative efficacy, while the latter “is intended to provide guidance for performing measurements of water activity,” and will “specify methods for qualification of instruments, calibration of instruments, methods for performing water activity measurements, and reporting of results.”
Technological innovation hasn’t slowed its pace since the introduction of USP <1112>, and water activity instruments have seen the benefits. Significant advances have been made – both adding new methods for measurement and improving existing ones.
One such advancement is the adoption of the tunable diode laser (TDL). Capable of isolating water’s signature on a molecular level, the TDL allows material scientists to make quick, direct measurements of previously unreadable, highly volatile substances. This enables researchers to use a greater range of substances to test hydrate formation and API stability without the risks associated with using theoretical data.
Other new instruments incorporate machine learning and AI to deliver readings in far less time – where older instruments require upward of 20 minutes, recent ones produce precise measurements in little more than one minute. In applications requiring repeated measurements, the time savings are significant.
Beyond reducing microbial risk and accelerating API stability research, water activity is now being used to maximize excipient effectiveness, develop and assess packaging, achieve ideal tablet hardness, influence dissolution rates and more.
As applications for water activity multiply, some begin to overlap with longer-established methods of measurement. Often, the investment in education and validation hinders water activity’s adoption to a new role, but in the long term, the speed, accuracy and usefulness of water activity bring significant returns.
Replacing Karl Fischer titration is the most obvious example, but perhaps the most misunderstood. Scientific investigation concludes that water activity is a far better predictor of product safety and stability than Karl Fischer water content. Even so, misconceptions continue – possibly because the relationship between moisture content and water activity can be counterintuitive.
A product with a high percentage of overall water content may have a very low water activity, or the other way around – a key factor when it comes to chemical and biological reaction rates.
Water activity does not provide the same information as Karl Fischer, but it does provide more useful information. The results will look different, but once understood, provide better correlations to microbial safety, chemical stability, and physical properties. Not only that, water activity instruments generally don’t require extensive training and leave comparatively little opportunity for mistakes during testing.
Though water activity’s relationship to other measurements like HPLC or GC differs, many of the same advantages apply – less need for training, quicker results, more direct measurements, less risk of instrument misuse, and no need for dangerous chemicals.
Water activity is more than a tool to meet regulatory standards. In the last few years, it has helped drive innovation, improve scientific productivity, and shorten the drug pipeline at many of the world’s largest pharmaceutical companies – and there are many more applications to be discovered.
Enigl, Davin C., and Kent M. Sorrells. “Water activity and self-preserving formulas.” Cosmetic Science And Technology Series (1997): 45-74.
Friedel, R. R. “The application of water activity measurement to microbiological attributes testing of raw materials used in the manufacture of nonsterile pharmaceutical products.” In Pharmacopeial forum, vol. 25, no. 5, pp. 8974-8981. United States Pharmacopeial Convention, 1999. Article link.
Heidemann, D. R., and P. J. Jarosz. “Preformulation Studies Involving Uptake in Solid Dosage Forms.” Pharmaceutical Research 8, no. 3. (1991): 292-97. Article link.
Pader, Morton. Oral hygiene products and practice. Dekker, 1988. Book link.
Pader, M. “Glycerine in oral care products.” Cosmetic science and technology series 11 (1991): 381-393. Article link.