PODCAST. Netanyahu al Congresso: più armi a Israele per continuare l’attacco a Gaza
@Notizie dall'Italia e dal mondo
Il leader israeliano ha respinto le critiche all'offensiva che ucciso più di 39.000 palestinesi, tra cui migliaia di bambini. Il servizio è di Michele Giorgio
L'articolo PODCAST. Netanyahu al Congresso: più armi a Israele per continuare
Chi è Jamie Dimon, da boss di JPMorgan al Tesoro con Trump
@Notizie dall'Italia e dal mondo
Il nuovo articolo di @Valori.it
Il banchiere, da sempre sostenitore democratico, potrebbe essere l'alfiere delle politiche fiscali espansive della presidenza repubblicana
L'articolo Chi è Jamie Dimon, da boss di JPMorgan al Tesoro con Trump proviene da Valori.
Hacking an IoT Camera Reveals Hard-Coded Root Password
Hacking — at least the kind where you’re breaking into stuff — is very much a learn-by-doing skill. There’s simply no substitute for getting your hands dirty and just trying something. But that doesn’t mean you can’t learn something by watching, with this root password exploit on a cheap IP video camera being a good look at the basics.
By way of background on this project, [Matt Brown] had previously torn into a VStarcam CB73 security camera, a more or less generic IP camera that he picked up on the cheap, and identified a flash memory chip from which he extracted the firmware. His initial goal was to see if the camera was contacting sketchy servers, and while searching the strings for the expected unsavory items, he found hard-coded IP addresses plus confirmation that the camera was running some Linux variant.
With evidence of sloppy coding practices, [Matt] set off on a search for a hard-coded root password. The second video covers this effort, which started with finding UART pins and getting a console session. Luckily, the bootloader wasn’t locked, which allowed [Matt] to force the camera to boot into a shell session and find the root password hash. With no luck brute-forcing the hash, he turned to Ghidra to understand the structure of a suspicious program in the firmware called encoder. After a little bit of poking and some endian twiddling, he was able to identify the hard-coded root password for every camera made by this outfit, and likely others as well.
Granted, the camera manufacturer made this a lot easier than it should have been, but with a lot of IoT stuff similarly afflicted by security as an afterthought, the skills on display here are probably broadly applicable. Kudos to [Matt] for the effort and the clear, concise presentation that makes us want to dig into the junk bin and get hacking.
Manually Computing Logarithms to Grok Calculators
Logarithms are everywhere in mathematics and derived fields, but we rarely think about how trigonometric functions, exponentials, square roots and others are calculated after we punch the numbers into a calculator of some description and hit ‘calculate’. How do we even know that the answer which it returns is remotely correct? This was the basic question that [Zachary Chartrand] set out to answer for [3Blue1Brown]’s Summer of Math Exposition 3 (SoME-3). Inspired by learning to script Python, he dug into how such calculations are implemented by the scripting language, which naturally led to the standard C library. Here he found an interesting implementation for the natural algorithm and the way geometric series convergence is sped up.
The short answer is that fundamental properties of these series are used to decrease the number of terms and thus calculations required to get a result. One example provided in the article reduces the naïve approach from 36 terms down to 12 with some optimization, while the versions used in the standard C library are even more optimized. This not only reduces the time needed, but also the memory required, both of which makes many types of calculations more feasible on less powerful systems.
Even if most of us are probably more than happy to just keep mashing that ‘calculate’ button and (rightfully) assume that the answer is correct, such a glimpse at the internals of the calculations involved definitely provides a measure of confidence and understanding, if not the utmost appreciation for those who did the hard work to make all of this possible.
Atollo Funafuti, Tuvalu
Circa a metà strada tra l’Australia e le Hawaii, la nazione insulare del Pacifico di Tuvalu è un arcipelago isolato composto da nove isole di corallo. Tutto sommato, la sua altitudine media è di 2 metri (6 piedi) sul livello del mare e la sua superficie ammonta a circa il 3 per cento di quella […]
Il bedrock colorato esposto in una scarpata di frana
Le pareti scoscese delle Valles Marineris a volte cedono, creando frane gigantesche. In questo modo si ottiene un’esposizione pulita del bedrock sottostante. Questa immagine della parete nord del Ganges Chasma rivela una roccia rugosa di diversi colori e tessiture, che rappresenta diverse unità geologiche. Fonte
Scoperta una nuova galassia di bassa massa
Immagine in falsi colori g+r dall’immagine Megacam di Corvus A. La regione blu di recente formazione stellare è chiaramente visibile sul lato orientale della galassia, ma c’è anche una popolazione sottostante di stelle più rosse. Gli astronomi hanno segnalato la scoperta di una nuova galassia nella costellazione del Corvus. La galassia scoperta, che ha ricevuto […]
Un’ambra birmana di 99 milioni di anni fa rivela la più antica lucertola conosciuta
Ricostruzione artistica di Electroscincus zedi; le aree della lucertola non rappresentate nel materiale disponibile sono rappresentate in modo sfocato. I paleontologi hanno trovato i resti di una specie di lucertola finora sconosciuta in un pezzo di ambra della metà del Cretaceo scavato nel nord del Myanmar. La specie appena scoperta era una piccola lucertola con […]
Scoperto un nuovo El Niño a sud dell’equatore
Secondo un nuovo studio, una piccola area dell’Oceano Pacifico sudoccidentale, vicino alla Nuova Zelanda e all’Australia, può innescare cambiamenti di temperatura che influenzano l’intero emisfero meridionale. Il nuovo modello climatico, che condivide alcune caratteristiche con il fenomeno El Niño, è stato denominato “Southern Hemisphere Circumpolar Wavenumber-4 Pattern”. A differenza di El Niño, che inizia ai […]
Secondo gli scienziati, i minerali contenenti metalli di terre rare sul fondo dell’oceano producono ossigeno
Un nodulo polimetallico, raccolto dal fondo dell’oceano, in un laboratorio della Northwestern University. I ricercatori della Scottish Association for Marine Science e i loro colleghi hanno scoperto che i fondali abissali ricoperti di noduli polimetallici nell’Oceano Pacifico producono il cosiddetto “ossigeno scuro”. I noduli polimetallici – depositi minerali naturali che si formano sul fondo dell’oceano […]
Tempesta di fulmini sulla Turchia
4 novembre 2023. Un astronauta a bordo della Stazione Spaziale Internazionale ha scattato questa fotografia di un temporale notturno sulla Turchia occidentale. L’immagine evidenzia due aree distinte di lampi, una a sud-est della città di İzmir e l’altra a nord di Aliağa. Utilizzando la funzione time-lapse della fotocamera e la giusta velocità dell’otturatore, gli astronauti […]
Le più antiche prove del campo magnetico terrestre trovate in Groenlandia
Le linee del campo magnetico terrestre. Recuperare antiche registrazioni del campo magnetico terrestre è una sfida perché la magnetizzazione delle rocce è spesso resettata dal riscaldamento durante la sepoltura tettonica nel corso della loro lunga e complessa storia geologica. I geologi del MIT e di altri Paesi mostrano che le rocce della cintura sovracrustale di […]
Gli astrofisici scoprono la connessione buco nero supermassiccio/materia oscura nella risoluzione del “problema del parsec finale
Simulazione della luce emessa da un sistema binario di buchi neri supermassicci in cui il gas circostante è otticamente sottile (trasparente). Vista da 0 gradi di inclinazione, ovvero direttamente sopra il piano del disco. La luce emessa rappresenta tutte le lunghezze d’onda. I ricercatori hanno scoperto un legame tra alcuni degli oggetti più grandi e […]
Le collezioni museali indicano che l’Europa centrale era un hotspot di biodiversità globale 15 milioni di anni fa
Le collezioni dei musei di storia naturale sono archivi unici dell’evoluzione. Ci permettono di guardare lontano nel passato geologico. Le conchiglie delle lumache marine sono fossili particolarmente comuni e ben si prestano a ricostruire la storia del clima e le distribuzioni marine precedenti. Un gruppo di lavoro guidato da Mathias Harzhauser (NHM di Vienna) si […]
Il paesaggio più bello di Marte
Molti paesaggi marziani presentano caratteristiche familiari a quelle che troviamo sulla Terra, come valli fluviali, scogliere, ghiacciai e vulcani. Tuttavia, Marte ha anche un lato esotico, con paesaggi estranei a quelli terrestri. Questa immagine mostra uno di questi luoghi esotici al Polo Sud. La calotta polare è costituita da anidride carbonica (ghiaccio secco), che non […]
Seguire la fauna selvatica di Palmyra
Vicino al centro geografico dell’Oceano Pacifico, le Isole della Linea si estendono attraverso l’equatore lungo un arco di 1.460 miglia (2.350 chilometri). Verso l’estremità settentrionale dell’arcipelago, a circa 1.000 miglia a sud delle isole Hawaii, la vegetazione, i banchi di sabbia e le scogliere poco profonde dell’atollo di Palmyra spiccano tra le acque blu tropicali. […]
Come il gas scolpisce i canali
Ogni inverno uno strato di ghiaccio secco ricopre i depositi stratificati del Polo Sud. In primavera, il gas creato dal riscaldamento del ghiaccio secco fuoriesce attraverso le fratture nel ghiaccio stagionale sovrastante, trascinando il materiale dal terreno sottostante. Il gas erode i canali della superficie, mostrati in questa immagine, sfruttando generalmente il materiale più debole. […]
XMM-Newton ci mostra il gas a milioni di gradi in Abell 2390
Gli scienziati hanno combinato l’immagine recentemente rilasciata da Euclide dell’ammasso di galassie massicce Abell 2390 con l’osservazione a raggi X di XMM-Newton dello stesso sito per mostrare il gas caldo e ardente che riempie lo spazio tra le galassie. Nell’immagine, la luce catturata da XMM-Newton appare come un bagliore blu che permea le distese tra […]
Gli astronomi individuano decine di nuove nane bianche pulsanti
Utilizzando il Transiting Exoplanet Survey Satellite (TESS) della NASA, gli astronomi hanno individuato 32 nuove nane bianche DA luminose e pulsanti della sottoclasse ZZ Ceti. La scoperta è stata riportata in un documento di ricerca pubblicato il 9 luglio sul server di pre-print arXiv. Le nane bianche (WD) sono nuclei stellari rimasti dopo che una […]
A Lenticular Clock Spells Out The Hours
So many are the clock projects which cross the Hackaday threshold, that it’s very rare indeed to see something that hasn’t already been done. We think we’ve not seen a lenticular clock before though, and we’re thus impressed by this one produced by [Moritz Sivers].
You may well be familiar with lenticular images from toys and novelties, an animation is sliced into lines and placed behind an array of multi-faceted linear lenses. It gives the effect of movement as from different viewing angles a different frame of the animation is perceived. In this clock the animation is replaced by the clock digits, and by rotating the whole with a servo driven by an ESP8266 microcontroller it can display different digits to the viewer. The write-up and the video below are of value both for the clock itself and the description of how these animations are produced. The clock itself doesn’t sacrifice usability for all its novelty, and we can see this technique might find a place in other projects requiring custom displays.
The lenticular lenses used here are off the shelf, but if you are of an adventurous mind, you could try printing some of your own.
Nei panni dell’hacker: simulare una ricognizione pre-attacco per prevenirne le mosse
Un attacco informatico può avere effetti devastanti sia in termini economici sia reputazionali e spesso ha successo perché gli hacker individuano vie di accesso ignorate da chi si occupa della sicurezza IT. Ma ci si può tutelare se si pensa e si agisce come un hacker
L'articolo Nei panni dell’hacker: simulare una ricognizione pre-attacco per prevenirne le mosse proviene da Cyber Security 360.
Isole nell’Universo
Questa immagine di Hubble ci offre un’istantanea meravigliosamente dettagliata di NGC 3430. Si tratta di una galassia a spirale che si trova a 100 milioni di anni luce dalla Terra, nella costellazione del Leone Minore. Diverse altre galassie si trovano relativamente vicine a questa, appena fuori dall’inquadratura; una è abbastanza vicina da far pensare che […]
Ecco come l’intelligenza artificiale sta cambiando la scienza dei rover marziani della NASA
In questo video time-lapse di un test condotto al JPL nel giugno 2023, un modello ingegneristico dello strumento Planetary Instrument for X-ray Lithochemistry (PIXL) a bordo del rover Perseverance Mars della NASA si posiziona contro una roccia per raccogliere dati. L’intelligenza artificiale sta aiutando gli scienziati a identificare i minerali all’interno delle rocce studiate dal […]
gaetaniumberto.wordpress.com/2…
Il super crash di Windows causato da un update errato di CrowdStrike: cosa impariamo
Un aggiornamento di CrowdStrike, rilasciato in produzione senza prima testarlo, ha messo in ginocchio aziende di mezzo mondo. Un blackout informatico mondiale che ci insegna che la resilienza aziendale passa anche e sempre più spesso attraverso la supply chain. Cerchiamo di capire cosa è successo e cosa serve per evitare che riaccada
L'articolo Il super crash di Windows causato da un update errato di CrowdStrike: cosa impariamo proviene da Cyber Security 360.
Uso della GenAI: come mitigare i rischi di esposizione di dati sensibili aziendali
Secondo l'ultimo Cloud and Threat Report di Netskope, triplica l'utilizzo in azienda della GenAI, alimentata sempre più da dati che le organizzazioni hanno il dovere legale di proteggere. Serve un maggior bilanciamento tra abilitazione sicura e gestione del rischio
L'articolo Uso della GenAI: come mitigare i rischi di esposizione di dati sensibili aziendali proviene da Cyber Security 360.
Maturity models per misurare la postura aziendale sulla privacy: cosa sono, come applicarli
È fondamentale avere pratiche, processi e procedure per governare l’etica e il modo in cui i dati vengono trattati dalle organizzazioni: il GDPR fornisce già molte indicazioni, ma a poco serve metterle in atto senza la capacità di monitorarne l’efficacia, valutarne i risultati, i rischi e capire dove e come è necessario migliorare
L'articolo Maturity models per misurare la postura aziendale sulla privacy: cosa sono, come applicarli proviene da Cyber Security 360.
Cellebrite non può sbloccare gli iPhone con iOS 17.4 o successivo: ecco cosa sappiamo
Alcuni documenti trafugati all'azienda israeliana Cellebrite hanno svelato che i suoi strumenti tecnologici non sono in grado di sbloccare gli iPhone 15 e tutti quelli con iOS 17.4 o versioni successive. Anche sul fronte Android le rivelazioni sono interessanti. Ecco cosa è venuto fuori dal recente data leak
L'articolo Cellebrite non può sbloccare gli iPhone con iOS 17.4 o successivo: ecco cosa sappiamo proviene da Cyber Security 360.
AI Act, il ruolo delle Autorità di protezione dei dati: ecco i chiarimenti dell’EDPB
L’EDBP, con lo statement 3/2024 del 16 luglio 2024, ha chiarito quale deve essere il ruolo dei Garanti privacy nel quadro regolatorio dell’AI. Spieghiamo meglio
L'articolo AI Act, il ruolo delle Autorità di protezione dei dati: ecco i chiarimenti dell’EDPB proviene da Cyber Security 360.
Data protection: quando i dati sono più importanti dell’azienda stessa
La priorità nella predisposizione di un piano di cyber security è proteggere i dati da ogni possibile causa di compromissione, in modo da garantire la business continuity: un aspetto particolarmente rilevante quando si tratta di ambiti critici come, ad esempio, sanità e trasporti
L'articolo Data protection: quando i dati sono più importanti dell’azienda stessa proviene da Cyber Security 360.
Bug in Cisco SSM On-Prem consente di modificare le password utente: update urgente
Cisco ha scoperto e corretto una grave vulnerabilità nella sua piattaforma Smart Software Manager On-Prem (SSM On-Prem) che, in caso di sfruttamento, potrebbe consentire di modificare le password di qualsiasi utente, inclusi gli amministratori. Ecco perché è importante aggiornare subito l’applicativo
L'articolo Bug in Cisco SSM On-Prem consente di modificare le password utente: update urgente proviene da Cyber Security 360.
Analisi della sicurezza: cos’è e perché può aiutare le aziende a essere cyber resilienti
Una corretta analisi della sicurezza offre alle aziende gli strumenti utili per identificare, proteggere e risolvere gli eventi che minacciano il sistema IT, utilizzando dati storici e in tempo reale. Ecco di cosa si tratta e perché migliora la visibilità di ambienti complessi per una protezione proattiva
L'articolo Analisi della sicurezza: cos’è e perché può aiutare le aziende a essere cyber resilienti proviene da Cyber Security 360.
Direttiva NIS 2: 5 passi per rendere le aziende cyber resilienti
La direttiva NIS 2, il cui recepimento nella legislazione nazionale di tutti i Paesi dell'UE è attesa entro il prossimo 18 ottobre, richiede piani di sicurezza nazionali e team specializzati. Ecco come attuare la compliance delle organizzazioni italiane in cinque passaggi
L'articolo Direttiva NIS 2: 5 passi per rendere le aziende cyber resilienti proviene da Cyber Security 360.
A Puzzle for the Visually Impaired, or Blindfolded
There’s no reason why a visually impaired person can’t enjoy putting together a jigsaw puzzle. It just needs to look a little different. Or, in this case, feel different.
16-year-old [feazellecw] has come up with just the solution — a puzzle with pieces that have both a defining texture and a slant in the z-height to them. While there is no picture on the puzzle face to speak of, instead there is a satisfying end result. You could change it up and add a relief image if you wanted, as long as you still observed the diagonal lines, the z-slant, and the little hole in the bottom that helps differentiate it from the top.
As [feazellecw] says, it’s important to find a box to help keep the pieces together during assembly; a 3D-printed box would be a nice touch. Files for this 15-piece puzzle are available if you’d like to make one for yourself or someone else, but just the idea might inspire you to make your own variant.
Don’t like putting puzzles together? Build a robot to do it for you.
FLOSS Weekly Episode 793: Keeping an Eye on Things with Hilight.io
This week Jonathan Bennett and Aaron Newcomb chat with Jay Khatri, the co-founder of Highlight.io. That’s a web application monitoring tool that can help you troubleshoot performance problems, find bugs, and improve experiences for anything that runs in a browser or browser-like environment. Why did they opt to make this tool Open Source? What’s the funding model? And what’s the surprising challenge we tried to help Jay solve, live on the show? Listen to find out!
youtube.com/embed/Grw4rKe3jkA?…
Did you know you can watch the live recording of the show Right on our YouTube Channel? Have someone you’d like us to interview? Let us know, or contact the guest and have them contact us! Take a look at the schedule here.
play.libsyn.com/embed/episode/…
Direct Download in DRM-free MP3.
If you’d rather read along, here’s the transcript for this week’s episode.
Places to follow the FLOSS Weekly Podcast:
Supercon 2023: Jesse T. Gonzalez Makes Circuit Boards That Breathe and Bend
Most robots are built out of solid materials like metal and plastic, giving them rigid structures that are easy to work with and understand. But you can open up much wider possibilities if you explore alternative materials and construction methods. As it turns out, that’s precisely what [Jesse T. Gonzalez] specializes in.
Jesse is a PhD candidate at Carnegie Mellon’s Human-Computer Interaction Institute, and an innovator to boot. His talk at the 2023 Hackaday Supercon covers his recent work on making circuit boards that can breathe and bend. You might not even call them robots, but his creations are absolutely robotic.
Be Flexible
Jesse begins by teaching us about robotic surfaces. He shows us a demonstration video, in which a metal ball is juggled around on a silicone bubble surface. Typically, we might model robot actuation in our heads as involving simple grippers on the ends of industrial robot arms, but that’s a limiting view. As the demo shows, even a surface itself can be robotic, and can be used to generate textures or manipulate objects, for example.
In his own apartment, Jesse has taken this idea a step further—creating the idea of a robotic environment. At his home, he walks in the door and is greeted by his robotic wall, which extends out to create a shelf for his shopping. Another part of the wall steps up to act as a coat hook. His very home itself has become roboticized to help ease his tasks of daily living.
He draws comparison to the Disney movie Encanto, which depicted a very house itself that was alive. And so many other films have shown us similar over the years. Walls that transform to reveal hidden doors, transforming desks and chairs and the like. Typically, these concepts are the preserve of mere cartoons, but there’s value in exploring whether we could make these things a reality.
He notes that building large interactive surfaces can be quite difficult, and that he didn’t produce this complex structure overnight. He returns to the example of the roboticized silicone bubble surface. Building a large bubble surface requires using a solenoid for each bubble section you want to actuate, he explains. This doesn’t scale well. However, if you could instead make a printed circuit board that featured the valves as an integral component, that would greatly simplify the assembly. Producing a larger PCB with more integral valves would be much simpler then endlessly wiring up more discrete valves.
In Jesse’s pneuamtic bubble demo build, the valves work by electrostatic action, with a structure consisting of a PCB with electrodes and a conductive diaphragm. With no voltage applied, the valve is shut. Applying voltage across the PCB electrode and the diaphragm pulls the valve open, letting air through. Voltage can also be applied to an alternate electrode to attract the diaphragm the other way, sealing the valve shut. The valves operate with an actuation voltage of a few hundred volts, and can switch in 40 milliseconds or so.
The system was originally developed with the electrostatic diaphragm to act as a “lid” on a pressure port. However, the electrostatic force wasn’t strong enough to keep the simple valve design shut. Jesse realized flipping the design on its head was the way to go. Instead, the valves are naturally sucked closed by vacuum on the system. They can then be pulled open via electrostatic actuation.
The PCB-based assembly method allowed creating complex arrays of valves that could actuate all kinds of things. Examples demonstrated by Jesse include the aforementioned bubble surface, as well as a “wheel” that walks with pneumatically-actuated syringes.
Leaving The Plane
Jesse’s initial work in this space was all very planar. No surprise, given the PCBs he was using were rigid. However, he wanted to “leave the plane” to explore more complex geometries. With his collaborators Dr. Scott E. Hudson and Dr. Alexandra Ion, he figured that combining rigid plates with hinge joints was an easy way to create more three-dimensional structures through folding. Again, PCBs were at the heart of this work.
The group wanted to explore this concept on architectural scales, imagining ideas like walls that could transform their entire form into new useful shapes. In time, they developed a wall surface with multiple columns, each composed of individual rigid cells that join to their neighbor with hinges. By the cells changing their orientation relative to each other, the whole column can change its shape. The cells are made of rigid plates of FR4. Each cell is joined to its neighbor with a semi-circular clamp actuated by a servo, flexible mylar hinges, and flat flex cables for electronic connections. By altering the orientation of the clamp, the cells can lock together in a rigid orientation, or allow the hinges to flex in a mountain or valley orientation.
For now, actuating the wall columns is mostly handled with pre-scripted actions. However, Jesse believes capacitive sensing or other technologies could make the wall more effortlessly interactive. In any case, even at its current level of sophistication, the living wall structure is serving as an excellent talking point in Jesse’s apartment.
Fundamentally, Jesse’s techniques are all about using PCBs in ways that make it easy to assemble adaptive structures at scale. It’s like taking a look at the nascent technology that seems to show up in so many science-fiction movies, where rooms and furniture seem to bend and change to their owner’s will. Perhaps one day, that could be more of a reality with techniques like these.
Exploring Soap Films
While fluid dynamics sounds like a dull topic, SoapFilmScope promises to make it fun by using your cell phone to observe the interactions between sound waves and liquid membranes. You can make your own with some PVC pipe, some 3D-printed attachments, a speaker, and a few other odds and ends.
If your PVC pipe doesn’t match [DaniloR29’s] exactly, no problem. The files are in OpenSCAD so you can easily change them to suit your needs. One end of the PVC tee dips into soap solution to form a film — think like a soap bubble before you blow it out of the bubble wand. The other ends have the speaker and the cell phone camera.
While the effect is entertaining, there’s real science behind it. You can learn about acoustic propagation, interference, and diphasic patterns, among other things. This would be a fun classroom project or just something to pass the time on a rainy afternoon. Be careful, though. Taking these kinds of pictures can be addictive. If you’d rather make bubbles, why not make giant ones?
If you enjoy this sort of thing, [Danilo] also built the KaleidoPhoneScope, which you can see in action in the video below.
The Rise of The Disappearing Polymorphs
Science and engineering usually create consistent results. Generally, when you figure out how to make something, you can repeat that at will to make more of something. But what if, one day, you ran the same process, and got different results? You double-checked, and triple-checked, and you kept ending up with a different end product instead?
Perhaps it wasn’t the process that changed, but the environment? Or physics itself? Enter the scary world of disappearing polymorphs.
Point of No Return
Imagine you’re working at a laboratory that creates pharmaceuticals. You figure out the reactants and the chemistry involved to make a new drug. You design a production line, and your new factory starts churning out the drug in mass quantities. This goes well for years, until suddenly, the drugs stop working.
You run an analysis, and the drugs coming out of the factory aren’t what you designed at all. They’re a weird new form of the same chemical with a different crystal structure, and they’re no longer working the same way. What happened?
You’ve probably come across the case of a disappearing polymorph. This is where the original version of a chemical’s crystal structure becomes impractical or impossible to produce. Instead, you tend to end up with a new version instead, typically a more stable, lower-energy version. The mere presence of this newer, more stable version tends to convert the original version into the new form quite easily. Since the new form is more stable, it tends to become difficult to convert the product back to the original form, or functionally, to produce it at all.
Paroxetine Problems
A great case study exists in paroxetine hydrochloride, an SSRI medication. The initial form of the drug was developed in the 1970s, and was known as paroxetine anhydrate. It was produced as a hygroscopic, chalky powder. However, in 1984, a new version spontaneously popped up at sites in the UK that were scaling up production. The new ‘hemihydrate’ crystal form was more stable. Drug in the anhydrate form would spontaneously convert into hemihydrate whenever the two came into contact in the presence of water or mere humidity.
The issue caused legal problems down the line. Years later, other drug manufacturers wished to produce paroxetine, too. The patent on paroxetine anhydrate had ran out, so generic manufacturer Apotex moved to begin production. The issue was that the company found it could not produce the original form. Instead, its product inevitably came out as paroxetine hemihydrate. It’s believed that the Earth’s atmosphere had functionally become populated by trace amounts of paroxetine hemihydrate, to the point where any paroxetine anhydrate would immediately be transformed into the new structure.
By this time, GSK was the company that held a still-active patent on paroxetine hemihydrate. It sued Apotex, arguing that its generic pills contained paroxetine hemihydrate that had been created through the atmospheric seeding process. The courts accepted GSK’s submission on this point, but ruled in favor of Apotex’s right to continue producing its generic pills. It was noted Apotex could not be held responsible for the issue of uncontrolled crystal seeding.
Later research saw two separate companies independently create another polymorph. Both Synthon and SmithKline Beecham sought patents for the production of polymorphs known as paroxetine mesylate. However, a similar problem cropped up shortly after. Any attempt to create the Synthon polymorph would end up creating the Beecham structure instead. This lead to much confusion over whether Synthon’s version was a new case of a disappearing polymorph, or whether the company had made errors in its patent work. Ultimately, no satisfying consensus was reached as to the truth of the matter.
Treatment Failure
Sadly, disappearing polymorphs can create more than legal woes. Ritonavir was released for public use in 1996, a crucial antiretroviral drug used in the fight against HIV. In its original crystal form, known as ‘Form I”, it was quite soluble and medically useful for treating the condition. However, in 1998, “Form II” was discovered. This was a more stable polymorph that existed at a lower energy level. The problem was that this crystal form was much less soluble. This made the drug less bioavailable, ruining its effectiveness at treating the disease.
The existence of Form II threatened the production of the useful form of the drug. Any laboratory that saw the introduction of Form II was unable to produce Form I afterwards. It was speculated by researchers that individuals that had worked in such labs could carry traces of the new form, and potentially poison facilities that were still producing Form I. In the space of a few weeks, everywhere that could once produce Form I was rapidly turning out only Form II instead.
Due to problems with production and the lack of efficacy of Form II ritonavir, the drug was pulled from the market. This lead to thousands of patients going without medication for their condition, and losses of over $250 million for the manufacturer, Abbott. The company held press conferences that highlighted the gravity of the issue.
“This is why all of us at Abbott have been working extremely hard throughout the summer [of 1998], often around the clock, and sometimes never going home at night. We have been here seven days a week and we will continue to do so. We have cancelled vacations and asked our families for their understanding and support. This is not an issue that we take lightly.”
Eventually, the problem was overcome. Researchers found a way to produce Form I under highly controlled conditions. The product had to be sold in a special refrigerated gel cap, compared to its original delivery form of a non-refrigerated capsule. Later developments included a combination of lopinavir and ritonavir that did not require lower temperatures to remain stable, and a new form of melt-extruded Form I ritonavir tablet that hit the market in 2010.
What Can Be Done
Scientists are some what at the mercy of nature when it comes to disappearing polymorphs. New polymorphs can pop up without warning, while tiny seed crystals can quickly contaminate entire labs, factories, and indeed, the world. There’s little defence. The only solution is doing hard chemistry—either to find ways to make original polymorphs survive the new world, or to find other new polymorphs that are still useful and still producible.
Ultimately, though, new polymorphs can be a pharmaceutical engineer’s nightmare. They can ruin a drug and ruin a factory overnight. Stories of ritonavir and other drugs will remain cautionary tales for this very reason.